Abstract
Background/Aim: Radical esophagectomy after preoperative neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, careful treatment selection is required when considering organ function in elderly patients. Prealbumin, a rapid turnover protein, is a short-term dynamic nutritional index, and its relationship with long-term postoperative survival in various cancers has been previously reported. However, the association between serum prealbumin level before NAC and survival in elderly patients remains unclear. This study investigated the clinical significance of prealbumin level measurement before NAC in elderly patients with locally advanced ESCC who underwent surgery after NAC. Patients and Methods: Eighty patients aged ≥65 years diagnosed with cStage II/III ESCC and undergoing radical esophagectomy after cisplatin and 5-fluorouracil therapy as NAC, were included. The cutoff value of the serum prealbumin level before NAC was set at 18.2 mg/dl using receiver operating characteristic curve analysis, and postoperative complications, recurrence, and overall survival were compared between the low and high prealbumin groups. Results: There were no differences in patient background, clinicopathological characteristics, postoperative complications, or recurrence-free survival between the two groups. Overall survival (OS) was significantly worse in the low prealbumin group than in the high prealbumin group (5-year survival, 33.3% vs. 67.0%; p=0.0341). Furthermore, on univariate and multivariate analysis, low prealbumin level was an independent poor OS factor (p=0.036). Conclusion: In elderly patients with locally advanced ESCC, serum prealbumin level before NAC may be a useful prognostic factor and may be important in selecting a treatment strategy that considers individual organ function.
Esophageal cancer (EC) is the eighth most common cancer among all carcinomas and the sixth leading cause of death among all carcinoma-related deaths globally (1). The standard treatments for EC are surgery, chemotherapy, and radiation therapy alone or in combination (2). Despite improvements in diagnostic techniques and therapeutic advances, treatment outcomes for locally advanced EC remain unsatisfactory (3). In Japan, the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemotherapy (NAC) followed by esophagectomy with optimal lymph node dissection and postoperative adjuvant chemotherapy in cases of positive lymph node metastasis (4). The results of the Japanese Clinical Oncology Group (JCOG) 9907 showed that NAC plus surgery, a combination of cisplatin and 5-fluorouracil, was superior to surgery plus postoperative adjuvant chemotherapy (5). Furthermore, based on the results of JCOG 1109 (6), the recommendation of a three-drug combination consisting of cisplatin and 5-fluorouracil plus docetaxel NAC was adopted. However, even with these newer multimodality therapies, the results are still unsatisfactory. To determine a treatment strategy for elderly patients with locally advanced ESCC, it is important to predict survival using biomarkers (7-10) and implement personalized therapy.
Rapid turnover proteins (RTPs), such as prealbumin, retinol-binding protein, and transferrin, are used as short-term nutritional indicators because of their short half-lives and rapid metabolic turnover (11). Prealbumin has a short half-life of approximately 48 hours and a large range of variability, making it useful for monitoring nutritional status before and after surgery and for evaluating liver protein binding capacity (12, 13). Preoperative prealbumin levels have been reported to be an independent prognostic factor for various malignancies (14-17). In EC, serum prealbumin levels immediately before surgery have also been reported to be an independent prognostic factor (18). However, there are few reports on the association between serum prealbumin levels before NAC and survival in elderly patients.
Therefore, this study aimed to determine the association between pre-NAC serum prealbumin level and survival in elderly patients with locally advanced ESCC.
Patients and Methods
Patients. We retrospectively surveyed patients with EC who underwent esophagectomy at the Kanagawa Cancer Center from January 2011 to December 2018. The inclusion criteria were as follows: 1) age ≥65 years, 2) clinical stage II or III ESCC, 3) cisplatin and 5-fluorouracil therapy as NAC, and 4) complete resection (R0). The exclusion criteria were as follows: 1) NAC with drugs other than cisplatin and 5-fluorouracil therapy, 2) chemoradiotherapy, 3) incomplete resection (R1 or R2), and 4) esophagectomy as salvage therapy. Histopathological examination was performed via upper gastrointestinal endoscopy prior to NAC. Staging was performed via upper gastrointestinal endoscopy and computed tomography (CT) according to the 8th edition of the Union for International Cancer Control TNM classification (19).
Treatment and assessment. NAC was administered before surgery according to the protocol of Study 9907 of the Japanese Society of Clinical Oncology (5). NAC consisted of cisplatin and 5-fluorouracil administered twice every 3 weeks. Surgical resection was performed using the standard technique 4-6 weeks after completion of chemotherapy. Sub-total esophagectomy was performed via an open thoracotomy approach through a right thoracotomy or a thoracoscopic approach. Reconstruction was performed by anastomosis with the cervical esophagus in the retrosternal or posterior mediastinal tract using a subtotal gastric tube. Generally, lymph node dissection was performed in three areas and in two areas for ECs located in the lower thoracic or abdominal esophagus.
Postoperative follow-up was conducted every 3 months for the first 3 years and every 6 months for the following 4 and 5 years. Physical examination, blood chemistry including tumor markers, and CT scans of the neck and abdomen were performed to evaluate EC recurrence.
Data collection. All clinicopathological, operative, and survival data were collected retrospectively from clinical databases and records. Postoperative complications that occurred during hospitalization or within 30 days after surgery were retrospectively identified from patient medical records and defined as grade II or higher according to the Clavien-Dindo classification (20).
Measurement of serum prealbumin levels. Serum prealbumin levels were measured in blood samples before the start of preoperative NAC. The cutoff values for survival and death were defined using a receiver operating characteristic curve analysis. The cutoff value for serum prealbumin level was 18.2 mg/dl. Patients were divided into high and low prealbumin groups according to the cutoff value.
Statistical analyses. Statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). Two-sided p-values <0.05 were considered statistically significant. Continuous variables were compared using Student’s t-test, and categorical variables were compared using chi-square analysis or Fisher’s exact test. The relationship between high and low prealbumin groups and overall survival (OS), cancer-specific survival (CSS), and relapse-free survival (RFS) was assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were conducted using Cox proportional hazards models to determine prognostic risk factors.
Ethical approval. Approval was obtained from the Institutional Review Board of Kanagawa Cancer Center prior to the start of this study (Approval No.: 2022 Epidemiological Study-147). Written informed consent for the use of clinical data, without identifying personal information, was obtained from each patient before surgery.
Results
Patients’ characteristics. The relationship between clinical characteristics in the low and high prealbumin groups is summarized in Table I. The median serum prealbumin levels were 25.8 mg/dl in the high prealbumin group and 16.6 mg/dl in the low prealbumin group (p<0.001). Apart from serum prealbumin levels, no significant differences were observed between the two groups. The frequency of postoperative complications did not differ between the two groups (Table II).
Characteristics of patients in the low and high prealbumin groups.
Postoperative complications.
Survival analysis. The low prealbumin group had significantly worse OS than the high prealbumin group (33.3% vs. 67.0%, respectively; p=0.034; Figure 1A). CSS was not significantly different between the two groups (55.3% vs. 74.0%, respectively; p=0.181; Figure 1B). Similarly, RFS was not significantly different between the two groups (42.7% vs. 55.7%, respectively; p=0.230; Figure 1C).
Kaplan-Meier survival curves for overall survival (OS) (A), cancer specific survival (CSS) (B), and relapse-free survival (RFS) (C) in patients with high and low prealbumin levels. Regarding the 5-year OS, the low prealbumin group had significantly worse OS than the high prealbumin group (33.3% vs. 67.0%, respectively; p=0.034). The 5-year CSS was not significantly different between the two groups (55.3% vs. 74.0%, respectively; p=0.181). The 5-year RFS was not significantly different between the two groups (42.7% vs. 55.7%, respectively; p=0.230).
Univariate and multivariate analyses of the clinicopathological factors for OS. In the univariate analysis, clinical stage and low prealbumin levels were significant prognostic factors for OS. In the multivariate analysis, clinical stage and low prealbumin levels were significant independent prognostic factors for OS [hazard ratio (HR)=2.548, 95% confidence interval=1.284-5.054, p=0.007; HR=2.075, 95% confidence interval=1.050-4.100, p=0.036, respectively; Table III].
Univariate and multivariate Cox proportional hazards analyses of the clinicopathological factors for the overall survival.
Discussion
This study investigated whether serum prealbumin level before NAC was associated with postoperative complications, recurrence, and long-term postoperative survival in elderly patients with locally advanced ESCC. The results showed that serum prealbumin level before NAC in elderly patients with locally advanced ESCC was not associated with postoperative complications or recurrence but was significantly associated with long-term postoperative survival. In addition, OS in the low prealbumin level group before NAC was significantly worse than that in the high prealbumin level group. Furthermore, in the multivariate analysis, low prealbumin level was selected as an independent prognostic factor for OS.
The cutoff value of prealbumin, identified by performing receiver operating characteristic curve analysis for survival and mortality, was 18.2 mg/dl. In previous reports showing the relationship between prealbumin level and survival in patients with gastric cancer, hepatocellular carcinoma, and urothelial carcinoma, 14-20 mg/dl has been used as the cutoff value (21-23). In addition, in previous reports showing the relationship between preoperative prealbumin level and survival rate in patients with EC and esophagogastric junction cancer, 18-21 mg/dl was used as the cutoff value (24-26). The cutoff value used in the current study falls within the range established by these previous reports.
In the present study, there was no significant association between preoperative prealbumin levels and the occurrence of all complications, including infectious complications. Low preoperative prealbumin levels have been reported to be a risk factor for the development of complications in various cancer and cardiac surgeries (27-29). However, low preoperative prealbumin levels in orthopedic surgery have been reported to be unrelated to complications, and no significant relationship between preoperative prealbumin levels and postoperative complications has been reported (30), which is consistent with our results.
In addition, we found no significant difference in RFS based on pre-NAC prealbumin levels in elderly patients with locally advanced ESCC; nor was there an association with recurrence. In contrast, it has been reported that low preoperative prealbumin level is an independent factor for poor RFS in patients with hepatocellular carcinoma (15, 31) as well as an independent factor for OS and RFS in patients with gastric cancer (21). However, low preoperative serum prealbumin level was reported to be associated with recurrence in patients with colorectal cancer but not an independent factor for recurrence (32). Furthermore, it has been reported that low preoperative prealbumin level was not associated with the risk of recurrence in patients with breast cancer (33). These findings underline the variability in the relationship between preoperative prealbumin levels and recurrence according to the type of cancer.
In the present study, pre-NAC prealbumin levels were associated with OS in elderly patients. It has also been reported that prealbumin level immediately before surgery was an independent prognostic factor for OS in ESCC without preoperative treatment (19, 26), consistent with the association of preoperative prealbumin level with OS in various cancer types (34-37).
The findings of our study indicate that low pre-NAC prealbumin levels in the elderly are associated with OS but not with RFS. This suggests that pre-NAC malnutrition in the elderly may be more closely related to survival than to recurrent ESCC. Although the reasons for this are unclear, we infer from previous reports that low pre-NAC prealbumin levels in the elderly may be associated with survival but not with recurrence after ESCC surgery due to increased mortality from other causes of death resulting from continued malnutrition after surgery. Preoperative prealbumin levels in patients with EC have been reported to be lower in the elderly compared to those in the younger patients (38). Low prealbumin levels are associated with sarcopenia, and elderly patients may be more susceptible to sarcopenia (39). Furthermore, ESCC patients with sarcopenia have a poor OS, including death from other causes, while recurrence remains unaffected (40). Essentially, low prealbumin levels before NAC in elderly patients with ESCC are associated with postoperative sarcopenia, which does not affect recurrence but is associated with poor OS, including morbidity and mortality from other causes.
Elderly patients experience several comorbidities and impaired organ function compared to that of younger patients. Consequently, NAC may not be suitable for patients with impaired organ function. In our study, patients with low prealbumin levels before NAC had poorer OS. Therefore, assessing serum prealbumin levels before NAC in elderly patients with locally advanced ESCC may be helpful in determining the optimal treatment strategy for the disease and evaluating organ function.
The present study has the limitation of being retrospective and conducted at a single institution. Therefore, to validate the association between prealbumin before NAC and survival in the elderly, a multicenter, prospective, large cohort study is needed.
Conclusion
Our study showed that serum prealbumin level before NAC in elderly patients with locally advanced ESCC was not associated with postoperative complications or recurrence but was significantly associated with long-term postoperative survival. Therefore, serum prealbumin level before NAC may be a useful prognostic factor in these patients. Evaluating serum prealbumin levels before NAC may be useful in determining individualized treatment strategies for locally advanced EC.
Acknowledgements
The Authors thank the patients, their families, and the staff at Kanagawa Cancer Center for their participation in this study.
Footnotes
Authors’ Contributions
Concept and study design: HS, TY, TO, and TO; Data collection and literature search: HS, SO, HI, SN, and TO; Data analysis and interpretation: HS, TY, IH, and TO. The manuscript and figures were drafted by HS and TO. The manuscript was revised and approved by all investigators. Thus, all the Authors actively participated in this study.
Conflicts of Interest
The Authors declare that there are no conflicts of interest regarding this study.
- Received August 24, 2023.
- Revision received October 14, 2023.
- Accepted October 16, 2023.
- 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).
