We enrolled 301 consecutive patients with stage I–III CRC diagnosed based on the 8th edition of the American Joint Committee on Cancer (AJCC) staging system26 and treated with curative resection at Teikyo University Hospital, Japan during the period 2012–2017. The surgery of all of the patients was elective. This retroprospective study was approved by the ethics of Teikyo University (Registation Number; 16-032). Informed consent was obtained from all participants, the reporting of our research is in accordance with the STROBE guidelines27.
The variables assessed included patient age, sex, tumor location, histological grade, TNM (tumor, nodes, metastasis) stage, personal medical history, preoperative laboratory data, early complications, and follow-up status. The CONUT score and the PNI were calculated on based on the patient’s preoperative laboratory data using. Early complications included anastomotic leakage surgical site infection, colitis, ileus, urinary tract infection, respiratory infection, and dysuria.
The following patients were excluded: (a) those who received adjuvant chemotherapy, (b) those with multiple primary malignancies , and (c) those with familial adenomatous polyposis or Lynch syndromes. Histopathological,clinical and laboratory data were obtained from the patients and blood sampling test was conducted within 1–2 weeks prior to the surgery. Total of 35 patients (neoadjuvant therapy 7, adenomatous polyposis 2, multiple primary malignancies 5 and data not available 21) were excluded (Fig. 5).
Each patient’s CONUT score was calculated using his/her data of serum albumin, total peripheral lymphocyte count, and total cholesterol concentrations, based on a previous report that used preoperative serum samples28. Albumin concentrations ≥ 3.5, 3.5 > and > 3.0, 2.99 > and ≥ 2.5, and < 2.5 g/dL were scored as 0, 2, 4, and 6 points, respectively; (2) total lymphocyte count ≥ 1,600, 1599–1,200, 1,199–800, and < 800/mm3 were scored as 0, 1, 2, and 3 points, respectively; and (3) total cholesterol concentrations ≥ 180, 140–179, 100–139, and < 100 mg/dL were scored as 0, 1, 2, and 3 points, respectively. The CONUT score was defined as the sum of items (1), (2), and (3). The CONUT score thus ranges from 0 to 12, with higher scores indicating a worse nutritional status.
The GPS score is as follows: hypoalbuminemia (< 35 g/L) and the elevated C-reactive protein (CRP) (> 10 mg/L) was given a score of 2. Hypoalbuminemia (< 35 g/L) or CRP > 10 mg/L was score of 1. Albumin concentrations ≥ 3.5 g/dL and CRP ≤ 10 mg/L was score of 09. However, hypoalbuminemia alone was not associated with reduced survival, so mGPS was created. The mGPS score 2 is hypoalbuminemia (< 35 g/L) and the elevated CRP (> 10 mg/L), score 1 was the elevated CRP (> 10 mg/L), score 0 is hypoalbuminemia (< 35 g/L) or serum albumin level (> 35 g/L) and the serum CRP lebel (< 10 mg/L)29.
The PNI, which is calculated using serum albumin and the peripheral lymphocyte count, is a simple and useful score for predicting the prognosis of patients with various cancers30. The PNI was calculated using the following formula: PNI = serum albumin level (g/dL) + 5 × total lymphocyte count21. Onodera reported that this index provided an accurate, quantitative estimate of operative risk31. In general, resection and anastomosis of the gastrointestinal tract can be safely practiced when the index is > 45. The same procedure may be dangerous when the index is between 45 and 40. When the PNI is < 40, this surgery may be contraindicated31. In other studies, the cutoff value of PNI was 40, which is common, We thus set the cut-off value for the PNI as 4021,32,33.
AIC (Akaike information criterion)
The AIC is a popular method for comparing the adequacy of multiple, possibly nonnested models34. A statistic that evaluates the predictability of a statistical model using the difference between the observed value and the theoretical value. The smaller the value, the better the fit35.
Surgical resection was defined as radical when there was no evidence of the tumor clearance and distant metastasis was both histologically and macroscopically complete. The patients were followed up every 3 months for the first 3 years, every 6 months for the next 2 years, and once annually thereafter. At each follow-up, all of the patients underwent a physical examination as well as the measurement of serum carcinoembryonic antigen (CEA) and CA19-9 (carbohydrate antigen 19-9). They also underwent full colonoscopies at 1–2 years after the surgery (retum cancer was every 1 year after surgery). Chest-abdominal computed tomography scans were generally obtained every 6 months. Recurrence was defined as the emergence of a radiological, clinical, and/or pathological diagnosis of cancer cells locally or distant from the original position.
Relapse-free survival (RFS) and overall survival (OS) were calculated from the date of the patient underwent surgery to that of recurrence or death, using the Kaplan–Meier method. A Cox regression analysis was performed to identify factors that are significantly associated with RFS or OS. Probability (p)-values ≤ 0.05 were considered significant. The Pearson product-moment correlation coefficient was used for the bivariate correlation. All statistical analyses were performed using JMP 14 software (SAS, Cary, NC, USA).
We conducted a receiver operating characteristic (ROC) curve analysis to determine the cut-off values for the CONUT score. At each value, an ROC curve was created by plotting the sensitivity and specificity of each result under study. The score closest to the point with both maximum sensitivity and specificity was chosen as the cutoff value, and the largest number of tumors was correctly classified for clinical outcome. There was a minor difference between the optimal cut-off values of RFS and those of OS, and we therefore used the cut-off values of the RFS for the OS in order to maintain consistency and prevent confusion.
The clinicopathological factors examined were as follows: sex, age, cancer location site (right side vs. left side), histology [tub 1 and tub 2 vs. others (por and pap etc.)], preoperative CONUT score, mGPS score, PNI, presence/absence of vascular invasion, presence/absence of lymph invasion pT category (T1, T2 vs. ≥ T3), pN category, tumor size, preoperative CEA level, preoperative CA19-9 level, and early complications.
The present study was conducted in accord with the Declarations of Helsinki and was approved by the Ethics Committee of the Teikyo University (approval date, 23 August 2016, Registration Number; 16–032).