Malnutrition has been considered to be associated with the prognosis of cancer. The Geriatric Nutritional Risk Index (GNRI), based on serum albumin levels, present body weight, and ideal body weight, is a simple screening tool to predict the risk of nutrition-related morbidity and mortality in elderly patients. We aimed to evaluate whether preoperative GNRI was associated with postoperative complications and prognosis in elderly patients with colorectal cancer (CRC). We retrospectively enrolled 313 CRC patients aged ≥65 years after curative surgery and classified them into an all-risk GNRI (≤98) group and a no-risk GNRI (>98) group. Kaplan-Meier analysis showed overall survival was significantly worse in the all-risk GNRI group than in the no-risk GNRI group (P = 0.009). Multivariable analyses showed low GNRI (≤98) was an independent risk factor for postoperative complications (P = 0.048) and overall survival (P = 0.001) in the patients. Among the complications, the incidence of surgical site infection, in particular, was significantly higher in the all-risk GNRI group (P = 0.008). In conclusion, low preoperative GNRI (≤98) was associated with increased postoperative complications and poor prognosis. Preoperative GNRI can be used as an identifier for potential high-risk group of morbidity and mortality in elderly CRC patients.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide[
Elderly patients often have some comorbidities, such as cardiovascular disease and respiratory dysfunction[
The Geriatric Nutritional Risk Index (GNRI) is an elderly-specific index that has been proposed to assess the nutrition-related risk of morbidity and mortality for elderly patients in hospital[
To date, there have been no reports on the relationship between GNRI and short- or long-term outcomes for elderly patients with CRC after surgery. Therefore, in this study, we investigated whether preoperative GNRI was associated with postoperative complications and prognosis for elderly patients with CRC who underwent curative surgery.
This study retrospectively enrolled 313 patients with CRC aged ≥65 years who underwent curative resection at Osaka University Hospital from August 2007 to December 2012. Patients who underwent curative resection for distant metastases were also included. Exclusion criteria for patients were as follows: (
The characteristics of 313 patients with CRC.
Variables Total (n = 313) Age (years)* 73 (65–94) Sex (male/female) 201/112 BMI (kg/m2)* 22.2 (8.7–33.6) ALB (g/dL)* 3.8 (1.9–4.8) WBC (/μL)* 5610 (2360–13700) CRP (mg/dl)* 0.07 (0.04–9.07) Preoperative CEA (ng/mL)* 3 (0.1–321) Preoperative CA19–9 (U/mL)* 11 (0–2505) Tumor location (colon/rectum) 239/74 Degree of differentiation (tub1/tub2/por/pap/muc) 132/156/14/1/10 Depth of tumor invasion (Tis/T1/T2/T3/T4) 29/73/58/136/17 Lymph node metastasis (N0/N1/N2) 225/65/23 Lymphatic vessel invasion (ly0/ly1/ly2/ly3) 117/163/29/4 Venous invasion (v0/v1/v2/v3) 238/62/12/1 Distant metastasis (none/HEP/PUL/LYM/PER) 304/6/0/1/2 TNM stage (0/I/II/III/IV) 29/115/77/83/9 Complication (CD grade) (none/I/II/III/IV/V) 249/23/23/16/2/0 GNRI 99.0 (62.2–122.6)
CRC = colorectal cancer, BMI = body mass index, ALB = serum albumin, WBC = white blood cell, CRP = C-reactive protein, CEA = carcinoembryonic antigen, CA19–9 = carbohydrate antigen 19–9, tub1 = well differentiated adenocarcinoma, tub2 = moderately differentiated adenocarcinoma, por = poorly differentiated adenocarcinoma, pap = papillary adenocarcinoma, muc = mucinous adenocarcinoma, HEP = liver, PUL = pulmonary, LYM = extra-regional lymph node, PER = peritoneal, TNM = tumor-node-metastasis, CD = Clavien-Dindo, GNRI = geriatric nutritional risk index, Asterisk values indicate median (range).
Clinicopathological factors such as age, sex, body mass index (BMI), serum albumin level (ALB), white blood cells, C-reactive protein (CRP), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), primary tumor location, distant metastases, pathological findings, and postoperative complications were collected from patients' medical records. Clinicopathological factors were classified according to the eighth edition of the Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) classification[
After surgery, all patients were followed up according to the Japanese guidelines[
The GNRI is a simple and objective screening tool for elderly patients' nutrition-related risk calculated using ALB, present body weight (PBW), and ideal body weight (IBW). IBW in this study was calculated as follows: IBW = height
Continuous variables were expressed as means ± standard deviation (SD) values. Differences between the classified GNRI groups and clinicopathological factors were analysed using chi-squared test or Fisher's exact test. The relationships between GNRI and each complication were also analysed by the same tests. Continuous variables with parametric distribution were analysed by Student's t-test or analysis of variance (ANOVA). Overall survival (OS) curves were plotted using the Kaplan–Meier method and compared using the generalised log-rank test. Univariate and multivariate analyses were performed using a logistic regression model to identify independent risk factors for postoperative complications and using a Cox proportional hazards regression model for OS. Receiver operating characteristic (ROC) curve analysis was used to predict the optimal cut-off value of GNRI for OS[
This study was performed in accordance with the principles of Declaration of Helsinki. This study was approved by the Institutional Review Boards of Osaka University and Osaka International Cancer Institute, and informed consent was obtained from all patients according to the guideline.
Two hundred one (64.2%) males and 112 (35.8%) females were included in this study. Characteristics of all patients are listed in Table 1. The median age was 73 years (range, 65–94 years). There were 29 (9.3%) patients with stage 0, 115 (36.7%) patients with stage I, 77 (24.6%) patients with stage II, 83 (26.5%) patients with stage III, and 9 (2.9%) patients with stage IV. The stage IV cases included liver metastasis (6 cases), extra-regional lymph node metastasis (1 case), and peritoneal dissemination (2 cases). Sixty-four (20.4%) patients had postoperative complications and 41 (13.1%) patients had those of CD grade ≥II.
The mean preoperative GNRI in 313 patients with CRC was 98.2 ± 9.6. Differences in the distribution of preoperative GNRI according to postoperative complications (CD grade ≥II) and TNM stages are shown in Fig. 1. The mean GNRI was 98.9 ± 9.2 in patients who had postoperative complications and 93.8 ± 11.0 in those without complications. There was a significant difference in preoperative GNRI between the two groups (P = 0.002) (Fig. 1a). The mean GNRI was 99.9 ± 7.1 in stage 0, 98.9 ± 8.8 in stage I, 97.3 ± 9.6 in stage II, 97.2 ± 11.3 in stage III, and 101.4 ± 9.1 in stage IV. There were no significant differences in preoperative GNRI among these stages (P = 0.390) (Fig. 1b).
Graph: Figure 1 Distribution of GNRI according to (a) postoperative complications (Clavien-Dindo grade ≥II) and (b) TNM stages. (a) GNRI is significantly lower in patients with postoperative complications than in those without them (P = 0.002). (b) GNRI is not significantly different among TNM stages (P = 0.390).
A previous study showed that a good sensitivity for risk prediction was found only for a GNRI cut-off value of 98[
Graph: Figure 2 Receiver operating characteristic (ROC) curve analysis of GNRI for overall survival in elderly patients with colorectal cancer. The ROC curve shows that the optimal cut-off value of GNRI is 98.082. Area under the curve for GNRI is 0.574. The sensitivity is 0.591, and the specificity is 0.569.
According to previous studies[
The relationship between GNRI status and clinicopathological factors in the elderly patients with CRC.
Variables GNRI All-risk ≤ 98 (n = 137) No-risk > 98 (n = 176) Age (≥73/<73) 83/54 88/88 0.062 Sex (male/female) 77/60 124/52 0.009* BMI (≥22/<22) 30/107 139/37 <0.001* ALB (≥3.5/<3.5) 75/62 169/7 <0.001* WBC (≥10000/<10000) 4/133 2/174 0.254 CRP (≥1/<1) 20/117 11/165 0.014* Preoperative CEA (≥5/<5) 45/92 51/125 0.462 Preoperative CA19–9 (≥38/<38) 22/115 17/159 0.090 Tumor location (colon/rectum) 102/35 137/39 0.485 Degree of differentiation (tub1, tub2/por, pap, muc) 127/10 161/15 0.691 Depth of tumor invasion (Tis, T1, 2/T3, 4) 71/66 89/87 0.825 Lymph node metastasis (present/absent) 41/96 47/129 0.530 Lymphatic vessel invasion (present/absent) 90/47 106/70 0.321 Venous invasion (present/absent) 35/102 40/136 0.563 Distant metastasis (present/absent) 3/134 6/170 0.517 TNM stage (0-II/III, IV) 95/42 126/50 0.665 Complication (CD grade ≥II) (present/absent) 25/112 16/160 0.018*
GNRI = geriatric nutritional risk index, CRC = colorectal cancer, BMI = body mass index, ALB = serum albumin, WBC = white blood cell, CRP = C-reactive protein, CEA = carcinoembryonic antigen, CA19–9 = carbohydrate antigen 19–9, tub1 = well differentiated adenocarcinoma, tub2 = moderately differentiated adenocarcinoma, por = poorly differentiated adenocarcinoma, pap = papillary adenocarcinoma, muc = mucinous adenocarcinoma, TNM = tumor-node-metastasis, CD = Clavien-Dindo, Asterisk values indicate P-values < 0.05.
A total of 41 patients had postoperative complications defined CD grade ≥II. These were surgical site infection (11 cases), ileus (8 cases), anastomotic leakage (7 cases), intra-abdominal abscess (5 cases), colitis (4 cases), pneumonia (3 cases), and urinary infection (3 cases). More patients had postoperative complications in the all-risk GNRI group (18.2%) than in the no-risk GNRI group (9.1%) (P = 0.018). The relationship between GNRI status and each complication was examined, and surgical site infection occurrence was higher in the all-risk GNRI group than in the no-risk GNRI group (P = 0.008) (Table 3).
The relationship between GNRI status and postoperative complications (CD grade ≥II) in the elderly patients with CRC.
Variables Total (n = 313) (%) GNRI All-risk ≤ 98 (n = 137) No-risk > 98 (n = 176) All 41 (13.1) 25 16 0.018* Surgical site infection 11 (3.5) 9 2 0.008* Ileus 8 (2.6) 4 4 0.720 Leakage 7 (2.2) 3 4 0.961 Intra-abdominal abscess 5 (1.6) 3 2 0.463 Colitis 4 (1.3) 3 1 0.202 Pneumonia 3 (1.0) 1 2 0.711 Urinary infection 3 (1.0) 2 1 0.423
GNRI = geriatric nutritional risk index, CD = Clavien-Dindo, CRC = colorectal cancer, Asterisk values indicate P-values < 0.05.
Univariate and multivariate analyses of clinicopathological factors for postoperative complications (CD grade ≥II) are shown in Table 4. According to the univariate analysis, high CRP (P = 0.032), tumor location (rectum) (P = 0.005), and low GNRI (P = 0.019) were significantly correlated with the complications. The multivariate analysis showed that tumor location (rectum) (P = 0.005) and low GNRI (P = 0.048) were independent risk factors for postoperative complications.
The univariate and multivariate analyses of predictors for postoperative complications (CD grade ≥II).
Variables Univariate Multivariate RR 95%CI RR 95%CI Age (≥73/<73) 1.518 0.770–2.993 0.228 Sex (male/female) 1.233 0.610–2.489 0.560 BMI (≥22/<22) 0.880 0.456–1.697 0.702 WBC (≥10000/<10000) 3.436 0.609–19.386 0.162 CRP (≥1/<1) 2.625 1.086–6.344 0.032* 2.471 0.980–6.231 0.055 Preoperative CEA (≥5/<5) 1.730 0.882–3.396 0.111 Preoperative CA19–9 (≥38/<38) 1.544 0.632–3.772 0.340 Tumor location (rectum/colon) 2.672 1.345–5.308 0.005* 2.741 1.356–5.539 0.005* Degree of differentiation (por, pap, muc/tub1, tub2) 1.292 0.420–3.974 0.655 Depth of tumor invasion (T3, 4/Tis, T1, 2) 1.758 0.898–3.439 0.100 Lymph node metastasis (present/absent) 1.067 0.518–2.199 0.860 Lymphatic vessel invasion (present/absent) 1.333 0.661–2.690 0.422 Venous invasion (present/absent) 1.794 0.886–3.632 0.105 Distant metastasis (present/absent) 0.825 0.100–6.773 0.858 GNRI (≤98/>98) 2.232 1.140–4.372 0.019* 2.001 1.002–3.999 0.048*
CD = Clavien-Dindo, RR = risk ratio, CI = confidence interval, BMI = body mass index, WBC = white blood cell, CRP = C-reactive protein, CEA = carcinoembryonic antigen, CA19–9 = carbohydrate antigen 19-9, por = poorly differentiated adenocarcinoma, pap = papillary adenocarcinoma, muc = mucinous adenocarcinoma, tub1 = well differentiated adenocarcinoma, tub2 = moderately differentiated adenocarcinoma, GNRI = geriatric nutritional risk index, Asterisk values indicate P-values < 0.05.
The median follow-up was 60.5 months (range, 1–137 months). Thirty-two death events and 105 censoring cases were recorded in the all-risk GNRI group, and 26 death events and 150 censoring cases were recorded in the no-risk GNRI group. OS rate was significantly worse in the all-risk GNRI group than in the no-risk GNRI group (P = 0.009) (Fig. 3). The 3- and 5-year OS rates in the all-risk GNRI group were 89.0% and 79.6%, and those in the no-risk GNRI group were 92.2% and 86.0%, respectively.
Graph: Figure 3 Kaplan-Meier analysis of overall survival according to GNRI. Overall survival rate is significantly worse in the all-risk GNRI (≤98) group than in the no-risk GNRI (>98) group (P = 0.009).
The univariate and multivariate analyses of clinicopathological factors for OS are shown in Table 5. According to the univariate analysis, sex (male) (P < 0.001), high preoperative CEA (P < 0.001), high preoperative CA19-9 (P < 0.001), depth of tumor invasion (T3, 4) (P < 0.001), lymph node metastasis (P < 0.001), lymphatic vessel invasion (P < 0.001), venous invasion (P < 0.001), distant metastasis (P < 0.001), and low GNRI (P = 0.010) were significantly correlated with OS. The multivariate analysis showed that sex (male) (P < 0.001), high preoperative CEA (P = 0.044), lymph node metastasis (P = 0.025), distant metastasis (P = 0.030), and low GNRI (P = 0.001) were independent prognostic risk factors for OS.
The univariate and multivariate analyses of prognostic factors for overall survival.
Variables Univariate Multivariate HR 95%CI HR 95%CI Age (≥73/<73) 1.627 0.957–2.851 0.073 Sex (male/female) 2.992 1.545–6.519 <0.001* 3.668 1.850–8.137 <0.001* BMI (≥22/<22) 1.224 0.727–2.100 0.451 Preoperative CEA (≥5/<5) 2.446 1.454–4.102 <0.001* 1.875 1.018–3.416 0.044* Preoperative CA19–9 (≥38/<38) 3.387 1.817–5.974 <0.001* 1.963 0.953–3.806 0.067 Tumor location (rectum/colon) 1.217 0.654–2.140 0.520 Degree of differentiation (por, pap, muc/tub1, tub2) 1.581 0.607–3.404 0.318 Depth of tumor invasion (T3, 4/Tis, T1, 2) 3.112 1.786–5.700 <0.001* 1.282 0.624–2.749 0.506 Lymph node metastasis (present/absent) 3.036 1.808–5.097 <0.001* 1.976 1.089–3.624 0.025* Lymphatic vessel invasion (present/absent) 2.963 1.564–6.217 <0.001* 1.062 0.463–2.552 0.890 Venous invasion (present/absent) 3.371 1.983–5.658 <0.001* 1.844 0.997–3.385 0.051 Distant metastasis (present/absent) 8.131 3.303–17.262 <0.001* 3.055 1.122–7.507 0.030* GNRI (≤98/>98) 1.988 1.179–3.384 0.010* 2.429 1.414–4.230 0.001*
HR = hazard ratio, CI = confidence interval, BMI = body mass index, CEA = carcinoembryonic antigen, CA19–9 = carbohydrate antigen 19–9, por = poorly differentiated adenocarcinoma, pap = papillary adenocarcinoma, muc = mucinous adenocarcinoma, tub1 = well differentiated adenocarcinoma, tub2 = moderately differentiated adenocarcinoma, GNRI = geriatric nutritional risk index, Asterisk values indicate P-values < 0.05.
To verify whether GNRI could be used for the prediction, we performed the other center study using the patient data in Osaka International Cancer Institute. Characteristics of all the patients in the other dataset are listed in Supplementary Table 1. The median age was 72 years (range, 65–88 years). Fifty-three (24.3%) patients had postoperative complications of CD grade ≥II. The mean preoperative GNRI in the patients was 101.9 ± 9.2.
The univariate and multivariate analyses for the complications in the other center study are shown in Supplementary Table 2. According to the univariate analysis, tumor location (rectum) (P = 0.001), venous invasion (P = 0.047), and low GNRI (P < 0.0001) were significantly related to the complications. The multivariate analysis showed that tumor location (rectum) (P = 0.001) and low GNRI (P < 0.001) were independent risk factors for the complications.
Furthermore, Kaplan-Meyer curve analysis in the other center study also showed that OS rate was significantly worse in the all-risk GNRI group than in the no-risk GNRI group (P = 0.002) (Supplementary Fig. 1). The 3- and 5-year OS rates in the all-risk GNRI group were 83.7% and 77.6%, and those in the no-risk GNRI group were 96.7% and 91.1%, respectively. The univariate and multivariate analyses for OS are shown in Supplementary Table 3. According to the univariate analysis, lymph node metastasis (P = 0.004), distant metastasis (P = 0.001), and low GNRI (P = 0.005) were significantly related to OS. The multivariate analysis also showed that lymph node metastasis (P = 0.035), distant metastasis (P = 0.042), and low GNRI (P = 0.048) were independent prognostic risk factors for OS.
Our results showed that GNRI was associated with increased postoperative complications and poor prognosis of CRC in elderly patients. Malnutrition has been found to be an important risk factor for postoperative morbidity and mortality in malignant tumors[
There are several methods for assessing nutritional status, such as BMI, prognostic nutritional index, skeletal muscle mass index, and subjective global assessment. While these measures are relevant for the prognosis of cancer[
In contrast, the advantage of GNRI is that it is an objective and easily available predicting tool. The classification value of GNRI has already been proposed[
Previously, GNRI was considered as a prognostic predictor for length of stay in hospital[
Some reports used the modified GNRI classification according to the complications[
Postoperative complications after CRC resection have been reported to be associated with poor oncologic outcomes, even if they are mild or moderate (CD grade II)[
To the best of our knowledge, this is the first study to investigate the relationship between GNRI and outcomes in elderly patients with CRC. Our study demonstrated that low preoperative GNRI (≤98) was correlated with increased postoperative complications (CD grade ≥II) and worse OS compared with high GNRI (>98) and that low GNRI was an independent risk factor for morbidity and mortality. In addition, although we examined the relationship between GNRI and TNM stages, no significant correlation between them was found. Therefore, we considered that GNRI was also an independent prognostic factor that did not depend on TNM stage.
Several studies have suggested that preoperative nutritional status is an independent risk factor for anastomotic leakage and wound infection in patients with CRC[
Low ALB is correlated with poor prognosis of cancer[
There are some limitations to our study. First, this study was a retrospective study evaluated only a small number of patients and institutes, and also affected by some selection and information bias. Prospective multicenter studies should be performed. Second, there is no single definition of elderly patients. While we defined elderly patients as those aged ≥ 65 years in the present study, the life span has extended and the number of patients aged>80 years has been increasing. Similar analyses may also have to be performed in patients aged >80 years. Third, our study did not assess the influence of smoking behavior because of lack of the information. Smoking is well known as a risk factor of malnutrition, postoperative complications, and poor cancer prognosis[
In conclusion, our study demonstrated that low preoperative GNRI value (≤98) was associated with increased postoperative complications and poor prognosis in patients with CRC aged ≥65 years after curative surgery. Preoperative GNRI can be a useful tool to identify high-risk population of morbidity and mortality in elderly patients with CRC.
M.S., N.M., M.M. and Y.D. contributed to the conception and design of this study. M.S., T.O., H.T. and H.Y. collected the data. M.S., M.U., C.M. and T.M. analysed and interpreted the data. M.S., N.M. and S.F. wrote the manuscript. All authors discussed the results and approved the manuscript.
The dataset used and analysed in the present study is available from the corresponding author on reasonable request.
The authors declare no competing interests.
Graph: Supplementary Information.
Graph: Supplementary Information.
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