Abstract
Background/Aim: The albumin and derived neutrophil-to-lymphocyte ratio (Alb-dNLR) score, which combines an inflammation index with a nutritional index, has recently been reported as a useful prognostic marker in various cancers. However, evaluation of the usefulness of Alb-dNLR score in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (NACRT) has not been reported yet. Patients and Methods: This retrospective study included 69 patients with LARC undergoing NACRT followed by surgery between November 2005 and July 2020. The cutoff value of the Alb-dNLR score for relapse-free survival (RFS) was determined using a receiver operating characteristic curve. Patients were divided into high and low Alb-dNLR-score groups and analyzed for RFS and overall survival (OS). Results: A total of 10 patients had high Alb-dNLR scores, and 59 had low Alb-dNLR scores. The high Alb-dNLR-score group had significantly higher rates of open surgery (70.0% vs. 28.8%; p<0.026), greater intraoperative blood loss (2,009 g vs. 421 g; p<0.001), and longer postoperative hospital stays (70 days vs. 42 days, p=0.012) than those of the low-Alb-dNLR-score group. The high Alb-dNLR-score group further demonstrated significantly worse RFS and OS than the low Alb-dNLR-score group (both p<0.001). Multivariate analysis identified the Alb-dNLR score as the most independent prognostic factor for RFS (hazard ratio=5.27; 95% confidence interval=2.09-13.27; p<0.001). Conclusion: The Alb-dNLR score is a valuable prognostic marker for predicting the oncological outcomes in patients with LARC undergoing NACRT.
Neoadjuvant chemoradiotherapy (NACRT) has become the standard treatment for locally advanced rectal cancer (LARC) after the influential study by Sauer et al. (1).
Many studies reported the benefits of NACRT, including increased rates of complete surgical resection (R0 resection) and reduced risk of local recurrence (2-5). However, assessing the balance between treatment benefits and potential side effects before initiating NACRT is challenging. Therefore, reliable markers for predicting the response to NACRT and determining the prognosis in patients with LARC should be established.
Inflammation plays a crucial role in cancer progression and prognosis, and various inflammation markers have been identified as prognostic indicators in various cancers (6). One such is the neutrophil-to-lymphocyte ratio (NLR), which is defined as neutrophil count divided by lymphocyte count. Several studies have demonstrated the prognostic value of NLR in patients with LARC undergoing NACRT, particularly regarding overall survival (OS) (7-10). However, there is a lack of consensus on its association with relapse-free survival (RFS) because although some studies reported a significant association between NLR and RFS (7, 8), many others indicated no significant correlation (9, 10). Clinical trial databases often include leukocyte and neutrophil counts; however, lymphocyte counts may not be readily available. To address this limitation, Proctor et al. implemented a derived NLR (dNLR) (11). It was defined as neutrophil count divided by leukocyte count minus neutrophil count and reported as a simpler measurement than NLR (11). Further, dNLR was reported to have prognostic value in various cancers (12, 13).
Nutritional status is another critical factor influencing cancer progression and prognosis. The albumin-dNLR (Alb-dNLR) score combines serum albumin level, which is a marker of nutritional status, with the dNLR to assess both immune system function and nutritional status. The score has been reported as a marker of rheumatoid arthritis activity and prognostic factor for patients with coronary artery disease after percutaneous coronary intervention (14, 15). Recently, the Alb-dNLR score was reported as a valuable prognostic marker for OS in patients with esophageal squamous cell carcinoma undergoing esophagectomy and was shown to be a better prognostic marker than albumin or dNLR alone (16).
Although the Alb-dNLR score is expected to be a useful prognostic marker for various cancers, its potential significance in patients with LARC undergoing NACRT remains unclear. The current study aimed to evaluate the clinical significance of Alb-dNLR score in predicting oncological outcomes in patients with LARC undergoing NACRT.
Patients and Methods
Patients. We conducted a retrospective cohort study on patients with LARC who underwent NACRT followed by surgery at the Kobe University Hospital between November 2005 and July 2020.
A total of 73 patients who met the following criteria were included in the study: 1) histologically proven adenocarcinoma, 2) lower margin of tumor below the peritoneal reflection, and 3) cT3/4 or cN+ lesions without evidence of distant metastases. After excluding 4 patients with missing blood test data, 69 patients were finally included in the analysis.
The clinical stage was classified according to the American Joint Committee on Cancer/Tumor-Node-Metastasis system based on imaging modalities, such as endoscopy, computed tomography, magnetic resonance imaging, and positron emission tomography (17).
Pathological response to NACRT was judged as “good” in Grades 2 and 3, and “poor” in Grades 1a and 1b, based on the guidelines of the Japanese Society for Cancer of the Colon and Rectum (18). Postoperative complications were classified according to the Clavien–Dindo classification system (19).
This study was approved by the Institutional Review Board of Kobe University Graduate School of Medicine (IRB Reference No. B220101).
Treatment strategy. The NACRT regimen consisted of a total radiation dose of 45 or 50.4 Gy (25 or 28 fractions) and oral 5-fluorouracil (5-FU)-based chemotherapy, as described previously (20). Surgical intervention, either open or laparoscopic, was performed 6-8 weeks after completion of NACRT. Open surgery was performed in cases until 2010, whereas laparoscopic surgery was performed in all cases from 2011 onward. Lateral pelvic lymph node (LLN) dissection was performed concurrently when LLN metastasis was suspected based on the imaging before NACRT. Adjuvant chemotherapy was considered for all patients, regardless of the pathological outcomes. The Roswell Park regimens of intravenous 5-fluorouracil plus leucovorin (LV), oral uracil/tegafur plus l-LV, or oral capecitabine plus oxaliplatin were administered as adjuvant chemotherapy.
dNLR and Alb-dNLR scores. Blood tests were routinely performed at the first visit and within 2 weeks before surgery to measure the white blood cell count, neutrophil count, and albumin level. Clinicopathological data were retrospectively collected from the patients’ medical records.
As previously reported, the dNLR was defined as the neutrophil count divided by the leukocyte count minus the neutrophil count (11). Cutoff values for serum albumin and dNLR were determined using receiver operating characteristic (ROC) curves to assess their predictive value for RFS. According to the cutoff values of serum albumin and dNLR, Alb-dNLR scores were categorized into three groups as follows: Alb-dNLR score of 2 for patients with low serum albumin and high dNLR, Alb-dNLR score of 1 for patients with either of the two abnormalities, and Alb-dNLR score of 0 for patients with high serum albumin and low dNLR. The cutoff value for the Alb-dNLR score was determined based on the ROC curve for RFS, and patients were classified into either the high or low Alb-dNLR score group.
Statistical analysis. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics (21). Comparisons of categorical variables were performed using the chi-square test or Fisher’s exact test, as appropriate. Continuous variables are expressed as medians (ranges). Survival curves based on Alb-dNLR scores were generated using the Kaplan–Meier method, and the results were compared using the log-rank test. Univariate analyses were performed using the Cox proportional hazards regression models to identify independent prognostic factors for RFS. Variables with significant differences in univariate analysis were further evaluated using multivariate analysis. Statistical significance was set at p<0.05.
Results
The cutoff values for serum albumin and dNLR based on ROC curves for RFS were 3.5 g/dl and 2.012, respectively (Figure 1A and B). The cutoff value for the Alb-dNLR score based on the ROC curves for RFS was 1 (Figure 1C). The patients were classified into either the high Alb-dNLR-score group (Alb-dNLR score of 2, 10 patients) or the low Alb-dNLR-score group (Alb-dNLR score of 1 or 0, 59 patients).
Determination of the cutoff values for serum albumin (Alb) and derived neutrophil-to-lymphocyte ratio (dNLR) based on the receiver operating characteristic curves for relapse-free survival (RFS). (A) The cutoff value for serum albumin was 3.5 g/dl, which yielded a sensitivity of 40.9% and a specificity of 89.4%. The area under curve (AUC) value for RFS was 0.61. (B) The cutoff value for the dNLR was 2.012, which yielded a sensitivity of 63.6% and a specificity of 57.4%. The AUC value for RFS was 0.56. (C) The cutoff value of Alb-dNLR score was 2, which yielded a sensitivity of 36.4% and a specificity of 95.7%. The AUC value for RFS was 0.67.
Patient and tumor characteristics are summarized in Table I. No significant difference between the two groups was observed.
Patient and tumor characteristics.
The operative and postoperative outcomes are shown in Table II. Open surgeries were performed significantly more frequently in the high Alb-dNLR-score group than in the low Alb-dNLR-score group (70.0% vs. 28.8%, p<0.026). Intraoperative blood loss and length of postoperative hospital stay were significantly lower in the low Alb-dNLR-score group than in the high Alb-dNLR-score group (2,009 g vs. 421 g, p<0.001 and 70 days vs. 42 days, p=0.012, respectively). The pathological outcomes are summarized in Table III. No significant difference was observed between the two groups. The Kaplan–Meier curves for RFS and OS in patients with high and low Alb-dNLR scores are shown in Figure 2. RFS and OS were significantly worse in the high Alb-dNLR-score group than in the low Alb-dNLR-score group (p<0.001).
Operative and postoperative outcomes.
Pathological outcomes.
Kaplan–Meier curves for the relapse-free survival (RFS) and overall survival (OS) in patients with high and low albumin and derived neutrophil-to-lymphocyte ratio (Alb-dNLR) scores. (A) RFS for the high Alb-dNLR-score group was significantly worse than that for the low Alb-dNLR-score group (p<0.001). (B) OS for the high Alb-dNLR-score group was significantly worse than that for the low Alb-dNLR-score group (p=0.001).
Kaplan–Meier curves for RFS and OS, according to high vs. low serum albumin alone and high vs. low dNLR alone are shown in Figure 3. Patients with high serum albumin levels showed significantly better RFS and OS rates. When compared based on the dNLR alone, patients with low dNLR tended to have better RFS and OS than those with high dNLR, although the difference was not statistically significant.
Kaplan–Meier curves for the relapse-free survival (RFS) and overall survival (OS) of patients with high and low serum albumin level or derived neutrophil-to-lymphocyte ratio (dNLR) alone. (A) OS for the low serum albumin group was significantly worse than that for the high-serum albumin group (p=0.027). (B) OS for the high dNLR group tended to be worse than that for the low dNLR group (p=0.101).
Univariate and multivariate analyses were performed to identify the independent prognostic factors for RFS (Table IV). The pathological response, pathological Stage (ypStage), and Alb-dNLR scores were significant factors in the univariate analysis. In the multivariate analysis, ypStage and Alb-dNLR scores were identified as significant predictors, with the latter being the most significant factor for RFS.
Univariate and multivariate analyses for relapse-free survival.
Discussion
The dNLR is a superficial inflammation index first proposed by Proctor et al., which has been reported to be prognostically useful in various cancer types (11). The Alb-dNLR score, which combines an inflammation index with a nutritional index, was recently reported as a useful prognostic marker in esophageal and gastric cancers (16, 22). However, no report has evaluated the usefulness of the Alb-dNLR score in rectal cancer. Patients with LARC often receive NACRT; however, the therapeutic effect is unknown until the surgery completion. Our study indicated that higher Alb-dNLR scores are associated with worse RFS and OS in patients with LARC undergoing NACRT. Furthermore, the Alb-dNLR score was superior to serum albumin level or dNLR alone as a prognostic marker. To the best of our knowledge, this was the first study to demonstrate the usefulness of Alb-dNLR score in patients with LARC undergoing NACRT.
Recent studies have shown that inflammation is an essential factor in tumor progression (23). Neutrophils, one of the primary inflammatory cells, increase DNA damage, angiogenesis, and immunosuppression through the secretion of cytokines and are associated with cancer development, growth, metastasis, and recurrence (24). Many studies have reported that neutrophil counts in peripheral blood are elevated in patients with various cancers (25). Lymphocytes are closely involved in the immune response in cancer, and cytokines secreted by cancer cells have been suggested to promote lymphocyte apoptosis (26). Pretreatment lymphocytopenia has been reported to be associated with poor prognosis in ovarian and bladder cancers (26, 27). Therefore, NLR, a composite index of neutrophils and lymphocytes, is considered useful as a prognostic marker for cancer (7-10). The dNLR is a simplified measure of NLR with the same diagnostic value. In LARC, an elevated dNLR was reported to be associated with worse pathological and clinical outcomes (28, 29). In addition to NLR and dNLR, other inflammatory markers, such as the monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, C-reactive protein, and systemic immune-inflammation index have also been reported to be useful prognostic markers in LARC (30-32). However, dNLR is the simplest and most inexpensive inflammatory indicator.
Nutritional status is also a prognostic factor for cancer. Serum albumin level provides a simple way to estimate a patient’s nutritional status. Malnutrition and inflammation suppress albumin synthesis (33). Cancer induces inflammation, and disease progression often results in decreased food intake; therefore, patients with LARC are sometimes malnourished and have hypoalbuminemia. In addition, cytokines, such as interleukin-6 secreted by cancer cells, may suppress albumin production by hepatocytes, leading to hypoalbuminemia (34). Some reports have suggested that pretreatment serum albumin levels have practical prognostic value for a variety of cancers, including colorectal cancer (35-38). Serum albumin is also routinely examined and considered readily accessible. In general, serum albumin level of less than 3.5 g/dl is defined as hypoalbuminemia. The ROC analysis in this study also demonstrated cutoff values of 3.5 g/dl for serum albumin levels. However, the following points should be noted when evaluating serum albumin levels. First, the half-life of serum albumin is relatively long, making it difficult to assess changes in nutritional status over a short period (39). Second, non-nutritional factors, such as hydration status, may obscure the actual effects of nutritional deficiencies.
The pathological response to NACRT is known to be associated with RFS in LARC (1, 40). Thus, good responders to NACRT have better prognosis than bad responders (41, 42). However, this pathological response is not revealed until the completion of surgery. Furthermore, if the pathological response is poor, the tumor may progress during the treatment period. Therefore, predicting tumor response before initiating NACRT is a critical issue that may influence the treatment strategy. In our study, pathological response was a prognostic factor for poor RFS in univariate analysis, similar to the Alb-dNLR score. However, after multivariate analysis, the pathological response was no longer a significant prognostic factor for poor RFS. Contrastingly, the Alb-dNLR score remained the most significant factor even after multivariate analysis. Analysis using the Fisher’s exact test showed no correlation between the Alb-dNLR score and pathological response (p=0.093, data not shown). Hence, the pre-treatment Alb-dNLR score was an independent prognostic factor for RFS and might be a promising substitute for pathological response, which can only be judged after the completion of NACRT.
We measured the Alb-dNLR scores both before and after NACRT. The Alb-dNLR score after NACRT was a significant prognostic factor for both RFS and OS, although less significant than that before NACRT (data not shown). Prognostic information available before NACRT is more favorable for helping patients make treatment choices. Regarding the association between prognosis and changes in inflammatory markers during NACRT, several reports have shown that the elevation of lymphocyte counts during NACRT is associated with pathologic downstaging and favorable prognosis (43, 44). However, we found no correlation between RFS or OS and the change in Alb-dNLR scores in this study (data not shown).
Study limitations. First, since this study had a retrospective design and was performed on a small scale in a single institution, a potential bias might exist. Second, the cutoff values for Alb and dNLR in this study were determined using ROC analysis and are not universal. Large-scale studies would be required in the future to validate our findings. Therefore, the results of this study should be interpreted carefully.
In conclusion, the Alb-dNLR score could be a simple and valuable prognostic marker for predicting RFS and OS in patients with LARC undergoing NACRT. The Alb-dNLR score is particularly feasible and useful since it can be determined before the initiation of NACRT.
Acknowledgements
The Authors would like to thank Honyaku Center Inc. for English language editing.
Footnotes
Authors’ Contributions
Takeru Matsuda, Taro Oshikiri, and Singo Kanaji involved in the conception and design of study. Takashi Nakanishi, Ruichiro Sawada, and Hiroshi Hasegawa involved in data collection. Takashi Nakanishi and Kimihiro Yamashita participated in the analysis and interpretation of data. Takashi Nakanishi wrote the main manuscript. Takeru Matsuda, Hironobu Goto, Naoki Urakawa, and Yoshihiro Kakeji were responsible for providing critical revisions. All Authors reviewed the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest or financial ties to disclose in relation to this study.
Funding
No funding was obtained for this study.
- Received September 3, 2023.
- Revision received December 15, 2023.
- Accepted December 18, 2023.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
