Abstract
Aim: The aim of the present study was to clarify the efficacy of inflammation-based Glasgow prognostic score after surgery in patients with gastric cancer and to determine clinicopathological factors affecting score improvement. Patients and Methods: Participants in this retrospective study were 236 patients with gastric cancer who underwent gastrectomy at the Fukuoka University Hospital. The high-sensitivity inflammation-based Glasgow prognostic score (HS-GPS) (cut-off values: 0.3 mg/dl for C-reactive protein; 3.5 g/dl for albumin) were calculated before and 1 month after surgery, and correlated to clinicopathological parameters and prognosis after surgery. Results: HS-GPS was classified as normal (score 0) in 162 patients and abnormal (score 1 or 2) in 74 patients. Out of the 162 patients with normal HS-GPS before surgery, 62 showed abnormal HS-GPS after surgery, while 26 of the 74 patients with abnormal HS-GPS before surgery improved to normal HS-GPS postoperatively. Abnormal HS-GPS before (p<0.0001) and after (p=0.0002) surgery were unfavorable prognostic factors in univariate analysis. HS-GPS after surgery was an independent prognostic factor (p=0.0324) in multivariate analysis, but HS-GPS before surgery was not. In the sub-group with abnormal HS-GPS before surgery (but not normal HS-GPS before surgery), improved HS-GPS after surgery had a favorable prognostic impact in both uni- (p=0.0039) and multivariate analyses (p=0.0032). Conclusion: HS-GPS after surgery may be a valuable prognostic factor in patients with gastric cancer. Supplemental therapy represented by adjuvant chemotherapy might be required for gastric cancer patients showing no improvement in HS-GPS after gastrectomy.
Gastric cancer is the fourth most common malignancy worldwide and the second cause of cancer-related deaths in the East (1, 2). Gastrectomy with lymph node dissection is reported as potentially curative treatment and adjuvant chemotherapy using S-1 is suggested to prolong survival in patients with stage II-III gastric cancer (3, 4). However, the 5-year survival rate is very unfavorable and has been reported as approximately 20% (5, 6).
Inflammation-based Glasgow prognostic score (GPS) is calculated from serum concentrations of C-reactive protein (CRP) and albumin to reflect systemic inflammatory response and was initially reported as a prognostic factor in patients with inoperable non-small cell lung cancer by Forrest et al. (7, 8). In terms of gastric cancer, several studies have recently reported that preoperative GPS could predict prognosis in patients undergoing curative surgery (9-11). However, no investigations have described changes in GPS with surgical treatment or the utility of postoperative GPS as a prognostic parameter.
In addition, Proctor et al. recently suggested the possibility that high-sensitivity CRP measurement (cut-off: 0.3 mg/dl) might offer improved prognostic value compared with conservative GPS using 1.0 mg/dl as the cut-off value (12).
The present study, therefore, examined pre- and postoperative GPS adopting high-sensitivity CRP measurement in patients with gastric cancer who underwent gastrectomy and correlations with clinical outcomes and clinicopathological parameters.
Patients and Methods
Patients. A total of 592 patients with gastric cancer underwent gastrectomy at the Fukuoka University Hospital between January 1995 and December 2006 and were followed for more than 5 years. Out of these, 236 patients (164 men, 76 women), for whom serum levels of CRP and albumin were measured preoperatively and at 28-34 days postoperatively (i.e., for whom GPS could be calculated preoperatively and 1 month postoperatively), were enrolled in the present study.
Patients' characteristics. Median age of participants was 64 years (range=21-88 years). Histopathological type was differentiated in 112 cases, undifferentiated in 118 and mixed in six. Tumor was classified as stage I in 104 patients, stage II in 31, stage III in 61 and stage IV in 40, according to the tumor node metastasis (TNM) classification of the International Union against Cancer (UICC), seventh edition (13). The procedure performed was distal gastrectomy in 157 patients, total gastrectomy in 77 and partial gastrectomy in 2. In addition to the clinicopathological parameters mentioned above, blood and lymphatic vessel invasion, preoperative combined disease, postoperative morbidity, operation time, intraoperative blood loss and perioperative blood transfusion correlated with GPS.
In the present study, the CRP cut-off value for the evaluation of inflammation-based GPS was set as 0.3 mg/dl in accordance with the report by Proctor et al., and the resulting score was termed “high-sensitivity GPS” (HS-GPS) for convenience (12). Patients showing CRP ≤0.3 mg/dl and albumin ≥3.5 mg/dl received a HS-GPS of 0. In all others, the score was considered to be 1 or 2 because HS-GPS 1 and 2 showed similar survival (data not shown). HS-GPS just before surgery was adopted as preoperative HS-GPS and HS-GPS at 28-34 days postoperatively was evaluated as postoperative HS-GPS. Patients in whom HS-GPS recovered to 0 before 28 days postoperatively were evaluated as HS-GPS of 0.
Statistical analysis. Correlations between perioperative HS-GPS and clinicopathological parameters were analyzed statistically. Changes in perioperative HS-GPS were examined by dividing patients into subgroups with preoperative HS-GPS of 0 or 1+2 and factors affecting these changes were analyzed statistically. Overall survival was analyzed using the Kaplan-Meier methods in univariate analysis and Cox proportional hazards modeling in multivariate analysis. Values of p<0.05 were considered statistically significant.
Results
Correlation between HS-GPS and clinicopathological parameters. Out of the 236 patients, 162 were classified as preoperative HS-GPS 0 group and 74 were HS-GPS 1+2 group. Preoperative HS-GPS correlated significantly with pT (p<0.0001), pN (p<0.0001), pM (p<0.0001), pStage (p<0.0001), lymphatic invasion (p=0.0015) and blood vessel invasion (p<0.0001), and patients with more serious cancer progression tended to be classified to the HS-GPS 1+2 group (Table I).
By contrast, 126 patients were classified to the postoperative HS-GPS 0 group and 110 to the HS-GPS 1+2 group. Postoperative HS-GPS correlated significantly with age (p=0.0002), pT (p=0.0063), pN (p=0.0051), pM (p=0.0069), pStage (p=0.0069), lymphatic invasion (p=0.012) and blood vessel invasion (p=0.040), preoperative combined disease (p=0.041), postoperative morbidity (p<0.0001), operation time (p=0.0002), intraoperative blood loss (p<0.0001) and perioperative blood transfusion (p<0.0001), and patients with more progressive cancer, combined disease, morbidity, longer operation time, more blood loss and blood transfusion tended to be classified as HS-GPS 1+2 group after surgery (Table I).
Out of the 162 patients with preoperative HS-GPS 0, 62 changed to HS-GPS 1+2 after surgery and postoperative HS-GPS improved to 0 in 26 of the 74 patients in the preoperative HS-GPS 1+2 subgroup, although a significant correlation was seen between pre- and postoperative HS-GPS (p<0.0001) (Table II).
Prognostic impact of HS-GPS. Pre- (p<0.0001) and postoperative (p=0.0002) HS-GPS 1+2 groups showed a significantly more unfavorable prognosis compared to HS-GPS 0 groups after surgery according to univariate analysis (Figures 1A, B).
In multivariate analysis with the clinicopathological parameters reflecting cancer progression, pT (p=0.0329), pN (p=0.0016), pM (p=0.0008) and postoperative HS-GSP (p=0.0324), but not preoperative HS-GPS, represented independent prognostic factors (Table III).
Effect of surgery on HS-GPS. In the preoperative HS-GPS 0 group, high age (p=0.0077), postoperative morbidity (p=0.0002), longer operation time (p<0.0001) and intraoperative blood loss (p=0.0002) were the parameters associated with worsened HS-GPS after surgery (Table IV).
By contrast, younger age (p=0.033), fewer lymph node metastases (p=0.035), no preoperative concomitant disease (p=0.031), no postoperative morbidity (p=0.0016) and no blood transfusion (p=0.0013) were the parameters associated with improvement to postoperative HS-GPS 0 from preoperative HS-GPS 1+2 (Table IV).
Postoperative HS-GPS was not identified as a significant prognostic factor in the preoperative HS-GPS 0 group in uni- or multivariate analyses (Figure 2A, Table V). However, postoperative HS-GPS had a significant prognostic impact in the preoperative HS-GPS 1, 2 group in the univariate (p=0.0039) and multivariate analyses (p=0.0032), and improvement of HS-GPS by surgery was suggested to be associated with prolonged survival after surgery (Figure 2B, Table V).
Discussion
The original GPS was reported as the cumulative score of CRP (score: 0, <1.0 mg/dl; 1, ≥1.0 mg/dl) and albumin (score: 0, >3.5 mg/dl; 1, ≤3.5 mg/dl) and showed prognostic significance in patients with inoperative advanced lung cancer (7, 8) Recent modifications to the GPS have been reported to provide much greater prognostic impact (9, 14). McMillan et al. assigned a CRP level >1.0 mg/dl a score of 1 or 2 independent of serum albumin for a commonly accepted modified GPS (14). By contrast, Proctor et al. recently demonstrated that use of high-sensitivity CRP (using a cut-off of 0.3 mg/dl) enhanced prognostic impact (12). In fact, both the original GPS and modified GPS were applied in our series (data not shown), but the prognostic significance was greatly enhanced in the analysis using HS-GPS. We therefore adopted the CRP cut-off value of 0.3 mg/dl for HS-GPS in the present study.
Correlation between clinicopathological parameters and pre- or postoperative HS-GPS.
Survival after surgery in patients with gastric cancer. A) The preoperative HS-GPS 0 group showed significantly favorable prognosis compared with the preoperative HS-GPS 1+2 group (p<0.0001). B) The postoperative HS-GPS 0 group also showed significantly favorable prognosis compared with the postoperative HS-GPS 1+2 group (p=0.0002).
Survival after surgery in patients with gastric cancer. A) No significant difference in prognosis was seen between the postoperative HS-GPS 0 and HS-GPS 1+2 groups in the subgroup analysis of preoperative HS-GPS 0 (p=0.19). B) The improved postoperative HS-GPS 0 group revealed significantly favorable prognosis compared with the HS-GPS 1+2 group in the subgroup analysis of preoperative HS-GPS 1+2 (p=0.0039).
Correlation between pre- and postoperative HS-GPS.
To date, the utility of preoperative GPS as a prognostic predictor has been reported in gastric cancer and various other malignancies (9-11). These studies suggested that GPS could be a prognostic predictor not only for inoperable advanced cases as reported for lung cancer, but also for operable cases in gastric cancer, and the results seem to reach a consensus. In contrast, the correlation between GPS and cancer progression-related clinicopathological parameters has remained controversial, even though our results suggest a significant correlation and further examinations with large series are warranted (9-11). Gastrectomy is known as the only potentially curative treatment for patients with gastric cancer (3, 15). However, the prognostic efficacy of surgery for gastric cancer patients has not been examined to date. We, therefore, examined postoperative HS-GPS in gastric cancer patients in addition to preoperative HS-GPS, to assess the therapeutic efficacy of gastrectomy based on changes in HS-GPS. The present study appears to be the first to evaluate postoperative GPS in gastric cancer patients, although Crozier et al. reported that postoperative GPS in the acute postoperative period had no prognostic impact for colorectal cancer patients (16). We selected one month after surgery as the time point for postoperative examination to clarify the influence of inflammatory response based on cancer immunology or nutritional immunology, while excluding the effects of acute inflammation by surgical stress. In fact, postoperative HS-GPS revealed an enhanced and independent prognostic impact in gastric cancer patients compared to preoperative HS-GPS in both uni- and multivariate analyses in the present series. Interestingly, postoperative HS-GPS showed significant correlations with preoperative combined disease and postoperative morbidity, as well as parameters associated with surgical stress represented by operation time, blood loss and blood transfusion, whereas preoperative HS-GPS showed no such correlations.
Correlation between clinicopathological parameters and postoperative HS-GPS.
Multivariate analysis of prognosis after surgery.
Multivariate analysis of prognosis after surgery classified by preoperative HS-GPS.
In addition, it was noteworthy that postoperative HS-GPS had a significant prognostic impact in the preoperative HS-GPS 1+2 group, but not in the HS-GPS 0 group. Previous reports have suggested that some patients with malignancy are under conditions of low albumin and elevated CRP (17, 18). Our results suggested that removal of the cause of HS-GPS aggravation by gastrectomy might improve HS-GPS and prolong survival. Furthermore, among the clinicopathological parameters related to improved postoperative HS-GPS (i.e., younger age, pN, preoperative combined disease, postoperative morbidity and perioperative blood transfusion), surgeons can improve postoperative HS-GPS by avoiding postoperative complications and perioperative blood transfusion. Such information may prove very useful for surgeons, in that fundamental attitudes in surgery may contribute to long-term clinical and oncological outcomes through improved HS-GPS, as well as perioperative short-term clinical outcomes in gastric cancer patients.
By contrast, patients who failed to achieve improved HS-GPS in the preoperative HS-GPS 1+2 group displayed unfavorable prognosis in this series. Those patients might be under latent cancer-bearing condition, and poor nutrition and immune suppression might be continued after surgery. The therapeutic limitations of gastrectomy against gastric cancer as a systemic disease, as initially advocated by Meyer and Jauch et al., and might be suggested in cases where postoperative HS-GPS remains unimproved (19, 20). It was also suggested, by our results, that the failure cases in the HS-GPS improvement significantly tended to have lymph node metastasis in the present series. Sasako reported that adjuvant chemotherapy using S-1 could prolong overall and relapse-free survival, although the prognostic impact of adjuvant chemotherapy using other anticancer drugs after gastrectomy remained controversial (4, 21-23). Adjuvant chemotherapy against gastric cancer as a systemic disease should, thus, be considered for patients with postoperative HS-GPS 1+2 to improve the postoperative prognosis.
Key limitations of the present study were the retrospective nature of the analysis and the limited amount of patient data available. Out of the 592 patients with gastric cancer who underwent gastrectomy and for whom preoperative HS-GPS could be determined, blood data allowing for determination of postoperative HS-GPS at 1 month after surgery were only available for 236 patients. Clearly some degree of selection bias during the postoperative recovery process might be present. Furthermore, whether 1 month after gastrectomy represents a suitable time for the evaluation of postoperative HS-GPS, remains debatable.
In conclusion, the present results suggest the utility of postoperative HS-GPS to assess the efficacy and prognostic contribution of gastrectomy in patients with gastric cancer. Large, prospective studies involving multiple institutions are required to clarify the utility of postoperative HS-GPS for not only gastric cancer, but also for other malignancies.
- Received June 5, 2014.
- Revision received July 10, 2014.
- Accepted July 11, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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