Recent studies have revealed the Glasgow prognostic score (GPS) to aid in the prediction of postoperative outcome in colorectal cancer patients. However, whether GPS predicts poor prognosis in curative colorectal cancer patients has yet to be ascertained. Furthermore, there is no information on the association between GPS and adjuvant chemotherapy in stage II or III colorectal cancer patients. A total of 219 patients with stage II and III colorectal cancer were included in this trial. The modified GPS (mGPS) defined in this study was calculated on the basis of admission data as follows: patients with an elevated level of both C-reactive protein (0.5 mg/dl) and hypoalbuminemia (Alb <3.5 mg/dl) were allocated a score of 2, and patients showing 1 or none of these blood chemistry abnormalities were allocated a score of 1 or 0, respectively. The association between the mGPS and clinicopathological findings and survival was retrospectively assessed. The mGPS was significantly higher in patients with an advanced age, serosal invasion, advanced stage cancer and pre-operative high CEA levels. Kaplan-Meier analysis revealed that a higher GPS predicted a higher risk of postoperative mortality in stage II and/or III colorectal cancer patients. Multivariate analyses revealed that the mGPS was the most sensitive predictor of postoperative mortality in stage II/III or stage II, respectively. The prognosis of stage II patients with a higher mGPS was as favorable as that of patients with a lower mGPS when adjuvant chemotherapy was undertaken. Pre-operative mGPS is considered to be a useful predictor of postoperative mortality in patients with stage II and/or III colorectal cancer, independently of the CEA test or TNM system. Postoperative adjuvant chemotherapy may be recommended for stage II colorectal cancer patients with a high mGPS.
Colorectal cancer is the most common malignant disease worldwide. Despite potentially curative surgery, approximately 30% of patients develop metastases, even when adjuvant therapies, inclusing chemotherapy and radiochemotherapy, are administered (
C-reactive protein (CRP) is an acute phase reactant that acts as a surveillance molecule for the activation of the adaptive immune system. It is synthesized in hepatocytes and is up-regulated by cytokines such as interleukin (IL)-6 and tumor necrosis factor-α (
We previously reported that CRP levels reflect IL-6 production in colorectal cancer tissues and predict poor prognosis in colorectal cancer patients, particularly in stage I or II patients who are not usually candidates for postoperative adjuvant chemotherapy (
By contrast, it has long been recognized that low circulating albumin concentrations prior to surgery are associated with a poor outcome in patients with colorectal cancer (
Therefore, it is of interest that the combination of hypoalbuminemia and elevated CRP levels, as in the Glasgow prognostic score (GPS), have been shown to provide additional prognostic information for patients with advanced cancer in various organs, including colorectal cancer (
Therefore, in this study we first examined, using the GPS, whether the combination of an elevated CRP and hypoalbuminemia could identify a subset of stage II or III colorectal cancer patients with a poor prognosis who require postoperative adjuvant therapy. Second, we evaluated whether the use of adjuvant chemotherapy improves the survival of patients with a poor prognosis as predicted by the GPS.
Overall, 219 patients with stage II or III colorectal cancer who received potentially curative surgery at our institution between January 1995 and January 2005 were enrolled in this retrospective study. Curative resection was defined as the absence of any gross residual tumor from the surgical bed and a surgical resection margin that was pathologically negative for tumor invasion. Data were retrieved from operative and pathological reports. Follow-up data were obtained from the outpatient clinical database.
The study group comprised 136 men and 83 women aged 29–91 years (median 66; interquartile range 58–73). Staging was principally based on the UICC/TNM classification of colorectal cancer. Overall, 125 patients had stage II and 94 had stage III disease. Experienced pathologists from our institution participated in this study and verified the accuracy of the original diagnosis. Of the 219 registered patients, 110 had tumors located in the colon and 109 had tumors located in the rectum. The pathologic tumor diameter indicated the maximum microscopic length of the tumor, irrespective of the depth. Differentiated tumors were histologically observed in 200 patients and undifferentiated tumors in 19 patients. Lymphatic invasion was observed in 191 patients and vascular invasion in 96 patients. After 1997, 96 patients with a favorable performance status who gave informed consent received adjuvant chemotherapies. Starting 4 weeks after curative surgery, pyrimidine-fluoride-based regimens were administered for 0.5–1 years to patients classified as mainly stage III [stage II, 45/125 (36%); stage III, 51/94 (54.3%)].
The patients were followed up every 12–16 weeks for at least 5 years according to our standard protocol, which included tumor-marker studies, computed tomography, colorectal fiber examinations, ultrasonography and chest radiography. Bone scans were performed when bone metastasis was indicated. The median follow-up time was 52.7 months (mean 56.9±63.8). The clinicopathologic parameters studied for prognostic value were tumor size, T classification, vessel involvement, lymphatic invasion, lymph node metastasis and serum carcinoembryonic antigen (CEA) concentration.
Blood samples were taken for routine laboratory measurements of albumin and CRP before surgery. This is the standard practice for all patients with cancer in our institution. The coefficient of variation for these methods, over the range of measurement, was <5%, as established by routine quality control procedures. Patients who underwent non-elective surgery or pre-operative radiotherapy, succumbed within 30 days of surgery or showed clinical evidence of infection or other inflammatory conditions, were excluded from the study.
The GPS was determined as previously described (
Data are presented as the means ± standard deviation (SD). Comparisons were made using the non-parametric Mann-Whitney U test for continuous variables and the Chi-square test for categorical data. The correlations were analyzed by Spearman’s coefficient analysis. ROC analyses were performed to calculate the cut-off values according to the most accurate value obtained using Medcalc 7.2 for Windows (Mariakerke, Belgium). The survival probabilities were calculated using the product limit method of the Kaplan-Meier methods, considering treatment- and colorectal cancer-related mortality. The differences between two groups were determined using the log-rank test. The influence of each significant predictor identified by log-rank tests was assessed by multivariate analysis using Cox’s proportional hazards model. The statistical analyses were carried out using StatView 5.0 (SAS Institute Inc., Cary, NC, USA) for Windows. Two-sided p-values of <0.5 were considered statistically significant.
During the observation period, 37 patients succumbed to colorectal cancer. Overall, 57 patients had elevated CRP levels (>0.5 mg/dl) and 46 had hypoalbuminemia (<3.5 mg/dl). Of the 57 patients with elevated CRP levels, 26 (45.6%) also had hypoalbuminemia.
The results of the univariate analysis of postoperative mortality, using the same factors as those in
Furthermore, in stage II or III colorectal cancer, elevated mGPS was associated with poor survival (stage II, p=0.0068; stage III, p=0.034) (
The TNM staging system provides the most reliable information on prognosis and aids in the discrimination of patients with early stage disease from those with advanced stage disease. However, it is less accurate for predicting the prognosis of patients with an intermediate extent of tumor invasion. CEA is a complex glycoprotein that is up-regulated in approximately 90% of advanced colorectal cancers and contributes to the malignant characteristics of tumors (
Recently, the combination of hypoalbuminemia and elevated CRP levels (>1.0 mg/dl) (original GPS) has been shown to provide additional prognostic information for patients with curative or advanced colorectal cancer. In the present study, we defined that the cut-off value of CRP was 0.5 mg/dl according to the best predictive values calculated by ROC analyses (
This study aimed to determine whether the mGPS provides more accurate prognostic information than that offered by existing staging systems or tumor markers, such as CEA, in stage II/III colorectal cancer patients. In fact, we showed that mGPS was significantly associated with serosal invasion, pre-operative CEA level and TNM classification, which are established conventional prognostic factors. Furthermore, mGPS-positive was found to have independent prognostic value, whereas the prognostic values of CEA or TNM classification were influenced by other clinical factors.
Recent studies on various types of malignancies have emphasized the importance of examining multiple lymph nodes in determining prognosis. In colon and rectal cancer, staging accuracy and survival are improved by increasing the number of nodes examined and analyzed (
Surgical resection is highly effective for stage II colorectal cancer, but a significant proportion of these patients (25–30%) develop recurrence and succumb to the disease. Therefore, identifying sensitive prognostic markers in this subgroup of patients would prompt the use of postoperative adjuvant in these patients with poor prognosis and thus improve survival. In the present study, we demonstrated that pre-operative mGPS was an independent prognostic factor for patients with stage II colorectal cancer. This ability to identify patients with stage II colorectal cancer with a poor prognosis and who would benefit from adjuvant therapy to prevent recurrence could improve cancer survival. In fact, mGPS-positive patients showed a significantly worse prognosis compared to mGPS-negative patients when adjuvant chemotherapy was not used, while cancer-specific survival was improved in the mGPS-positive patients with the worst prognosis when adjuvant chemotherapy was used.
The mechanism of CRP up-regulation is controlled by cytokines, including IL-8, IL-6 and tumor necrosis factor-α (
Taken together, the results of the previous and present studies suggest that CRP is more than just an indicator of tumor burden in certain patients with colorectal cancer, in whom tumor burden and a deteriorated host-tumor interaction may synergistically elevate systemic induction of CRP. Elevated CRP levels may then enable the systemic formation of the IL-6sR/IL-6 complex and up-regulate IL-6-mediated tumor growth factors. The subsequent autocrine/paracrine stimulation of residual tumor cells protects cells from apoptosis and regrowth.
In conclusion, pre-operative mGPS levels may provide valuable prognostic information in patients with stage II and III colorectal cancer, and is independent of the CEA test or pathological N classification system. Accordingly, the mGPS may provide valuable information concerning specific subgroups of patients who might benefit from adjuvant chemotherapy for stage II colorectal cancer. However, further studies are required to confirm our results.
Receiver operating characteristic (ROC) curves for (A) peak serum CRP and (B) albumin (ALB) in patients with stage II and III colorectal cancer (n=219). The arrows indicate the location on the ROC curves for the diagnostic cut-off point that minimizes the misclassification of surviving and deceased patients. CRP: sensitivity 79.5%, specificity 51.1%, cut-off 0.5 mg/dl. ALB: sensitivity 80.7%, specificity 36.7%, cut-off 3.5 mg/dl.
Kaplan-Meier analysis of the 5-year survival rates of stage II and III patients according to (A) inflammatory status-based prognostic score (mGPS 0, 1 and 2), (B) with or without elevated serum CEA levels. mGPS, modified Glasgow prognostic score; CEA, carcinoembryonic antigen.
Receiver operating characteristic curves of (A) inflammatory status-based prognostic score (mGPS 0, 1 and 2) and (B) serum CEA levels in stage II and III colorectal cancer patients showing the best cut-off value to predict prognosis and AUC (CEA, 0.610; mGPS, 0.635). mGPS, modified Glasgow prognostic score; CEA, carcinoembryonic antigen; AUC, area under curve.
Kaplan-Meier analysis of the 5-year survival rates of patients with stage II (A) or stage III (B) colorectal cancer according to inflammatory status-based prognostic score (mGPS 0 vs. mGPS 1/2).
Evaluation of adjuvant chemotherapy in patients with stage II colorectal cancer who were predicted to have poor prognosis by mGPS. (A) Survival curves of stage II patients without adjuvant chemotherapy according to inflammatory status-based prognostic score (mGPS 0 vs. mGPS 1/2). (B) Survival curves of patients with stage II colorectal cancer treated with adjuvant chemotherapy according to inflammatory status-based prognostic score (mGPS 0 vs. mGPS 1/2).
Association between GPS and clinicopathological characteristics of stage II and III patients undergoing potentially curative resection for colon cancer.
Patients | GPS 0 | GPS 1 | GPS 2 | p-value | |
---|---|---|---|---|---|
Age (years) | |||||
≤64 | 95 | 72 | 17 | 6 | |
>64 | 124 | 70 | 34 | 20 | |
Gender | 0.9700 | ||||
Female | 83 | 53 | 20 | 10 | |
Male | 136 | 89 | 31 | 16 | |
Vascular invasion | 0.6320 | ||||
No | 123 | 83 | 27 | 13 | |
Yes | 96 | 59 | 24 | 13 | |
Lymphatic invasion | 0.4670 | ||||
No | 28 | 21 | 5 | 2 | |
Yes | 191 | 121 | 46 | 24 | |
Serosal invasion | |||||
No | 139 | 100 | 29 | 10 | |
Yes | 80 | 42 | 22 | 16 | |
Pathology | 0.9430 | ||||
Diff. | 200 | 129 | 47 | 24 | |
Non diff. | 19 | 13 | 4 | 2 | |
TNM stage | |||||
II | 125 | 89 | 20 | 16 | |
III | 94 | 53 | 31 | 10 | |
Chemotherapy | 0.5700 | ||||
No | 123 | 77 | 29 | 17 | |
Yes | 96 | 65 | 22 | 9 | |
CEA | |||||
≤6 | 134 | 100 | 26 | 8 | |
>6 | 85 | 42 | 25 | 18 |
GPS, Glasgow prognostic score; CEA, carcinoembryonic antigen.
Clinicopathological characteristics of stage II and III patients undergoing potentially curative resection for colorectal cancer: univariate survival analysis.
HR | 95% CI | p-value | |
---|---|---|---|
Age ( ≤64 vs. >64) | 1.02 | 0.530-1.95 | 0.9500 |
Gender (male vs. female) | 1.21 | 0.610-2.44 | 0.5600 |
Chemotherapy (yes vs. no) | 1.04 | 0.540-2.01 | 0.9000 |
Venous invasion (yes vs. no) | 1.17 | 0.600-2.32 | 0.6300 |
Lymphatic invasion (yes vs. no) | 1.15 | 0.430-3.05 | 0.8000 |
Lymph-node metastasis (yes vs. no) | 1.45 | 0.760-2.86 | 0.2500 |
Serosal invasion (yes vs. no) | 1.99 | 1.060-4.12 | 0.0300 |
Pathology (well vs. poor diff.) | 0.33 | 0.046-0.58 | 0.0050 |
CEA (≤6 vs. >6) | 2.66 | 1.460–5.63 | 0.0020 |
mGPS (0 vs. 1.2) | 0.33 | 0.140-0.58 | 0.0005 |
mGPS, modified Glasgow prognostic score; CEA, carcinoembryonic antigen.
Clinicopathological characteristics of stage II and III patients undergoing potentially curative resection for colorectal cancer: multivariate survival analysis.
HR | 95% CI | p-value | |
---|---|---|---|
Serosal invasion (no vs. yes) | 0.75 | 0.38-1.47 | 0.400 |
Pathology (poor vs. well diff.) | 2.89 | 1.25-6.69 | 0.013 |
CEA (≤6 vs. >6) | 0.54 | 0.27-1.08 | 0.080 |
mGPS (1,2 vs. 0) | 2.80 | 1.43-5.49 | 0.003 |
Clinicopathological characteristics and cancer-specific survival in patients undergoing potentially curative resection for stage II colorectal cancer: multivariate survival analysis.
HR | 95% CI | p-value | |
---|---|---|---|
Age (≤64 vs. >64) | 0.56 | 0.19-1.70 | 0.310 |
Gender (male vs. female) | 0.56 | 0.17-1.81 | 0.330 |
Chemotherapy (yes vs. no) | 1.52 | 0.48-4.82 | 0.480 |
Venous invasion (yes vs. no) | 0.64 | 0.19-2.11 | 0.470 |
Lymphatic invasion (yes vs. no) | 2.02 | 0.45-8.18 | 0.330 |
Serosal invasion (yes vs. no) | 0.93 | 0.33-2.63 | 0.890 |
Pathology (well vs. poor diff.) | 7.61 | 1.79-32.44 | 0.006 |
CEA (≤6 vs. >6) | 0.40 | 0.14-1.17 | 0.090 |
mGPS (0 vs. 1,2) | 5.01 | 1.60-15.69 | 0.005 |