|Year : 2014 | Volume
| Issue : 4 | Page : 799-804
The value of the systematic inflammation-based Glasgow Prognostic Score in patients with gastric cancer: A literature review
Yongyin Gao, Dingzhi Huang
Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
|Date of Web Publication||9-Jan-2015|
Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin
Source of Support: None, Conflict of Interest: None
The presence of a systemic inflammatory response (SIR) is recognized to occur in the presence of malignancy. And the SIR-Glasgow Prognostic Score (GPS)/modified GPS (mGPS) composed of the C-reactive protein (CRP) and albumin is a tumor stage- and treatment-independent, routinely available and well-standardized prognostic factor, reflects both an ongoing SIR (CRP) and a progressive nutritional decline (albumin) in patients with advanced cancer. Previous studies showed that GPS/mGPS appear to be a superior prognostic factor compared with other cellular components of the SIR and Eastern Cooperative Oncology Group performance status in some aspects. Besides, GPS/mGPS aids at deciding active or palliation treatment and selecting patients with gastric cancer who tolerate platinum-based chemotherapy. Therefore, GPS/mGPS may be incorporated or combined with other factors to improve assessment of prognosis and guide treatment of patients with gastric cancer in a routine clinical work. However, it remains to be determined whether the GPS and mGPS have different prognostic value in each stage of gastric cancer and the necessity of normalization of the GPS/mGPS by anti-inflammation and maintenance of performance status or nutritional status in clinical work.
全身性炎症反应（SIR）被公认为在恶性肿瘤的出现时发生。并且，在中晚期癌症患者中，由C反应蛋白（CRP）和白蛋白组成的SIR-格拉斯哥预后评分（GPS）/改良GPS（mGPS）是肿瘤分期和治疗不相关的，常规可用的和规范的预后因素，反映了一个持续的全身性炎症反应（SIR）/（CRP）和一个渐进的营养（白蛋白）下降过程。以往的研究表明，GPS /mGPS较其它细胞成分的SIR，表现为一个更好的预后因素，东部肿瘤协作组在一些方面也表现出其地位。此外，GPS /mGPS可以帮助决定或积极治疗还是保守治疗，选择可耐受铂类为基础的化疗的胃癌患者。因此，GPS / mGPS可以结合其他因素来提高在日常临床工作中胃癌患者的预后和指导治疗的评价。然而，在临床工作中，有待确定是，GPS/mGPS在胃癌的各个阶段是否有不同的预后值，以及通过抗炎和表现状态或营养状况维持的GPS /mGPS是否需要标准化。
Keywords: Gastric cancer, glasgow prognostic score, modified glasgow prognostic score, the prognostic value
|How to cite this article:|
Gao Y, Huang D. The value of the systematic inflammation-based Glasgow Prognostic Score in patients with gastric cancer: A literature review. J Can Res Ther 2014;10:799-804
|How to cite this URL:|
Gao Y, Huang D. The value of the systematic inflammation-based Glasgow Prognostic Score in patients with gastric cancer: A literature review. J Can Res Ther [serial online] 2014 [cited 2019 Nov 15];10:799-804. Available from: http://www.cancerjournal.net/text.asp?2014/10/4/799/146054
| > Introduction|| |
Gastric cancer is rampant in many countries around the world. By some estimates, it is the forth most common cancer worldwide.  However, it is often diagnosed at an advanced stage. Five-year survival for advanced or metastatic gastric cancer is around 5-20%, with median overall survival <1 year.  However, there is marked heterogeneity in the duration of survival among patients. Therefore, there have been continuing efforts to investigate the prognostic factors related to survival.  In addition, some patients suffer from the toxicities of chemotherapy and the high morbidity and mortality of surgical treatments, the appropriate selection of patients, most likely to benefit and that deciding whether active intervention or palliation is appropriate is of considerable importance. Thus, it is important to identify predictive factors of response to chemotherapy and prognostic factors for survival in these patients. 
It is widely accepted that Eastern Cooperative Oncology Group performance status (ECOG-ps), pathological tumor stage, the number of metastatic lymph nodes, depth of tumor invasion are common prognostic factors of predicting the prognosis and treatment outcome for cancer patients. However, weight loss is often not well-defined, and performance status is recognized to be subjective.  Therefore, the selection of weight loss or performance status as prognostic factor remains problematical. Besides, pathological tumor stage, the number of metastatic lymph nodes, depth of tumor invasion found to influence prognosis in gastric cancer patients can only be properly evaluated postoperatively. On the other hand, preoperative TNM causes the difficulty and bias for predicting survival preoperatively. All the facts mentioned suggest that the widely accepted common prognostic factors are still needed to be further perfected to better predict the prognosis and treatment outcome.
Recent studies have shown that the preoperative combination of neutrophil lymphocyte ratio (NLR) and circulating concentrations of C-reactive protein (CRP) might be useful to predict the prognosis of patients with nonsmall cell lung cancer (NSCLC).  In addition, hypoalbuminemia, a typical index of malnutrition, has been reported to be associated with poor survival in advanced cancer.  The Glasgow Prognostic Score (GPS), an inflammation-based prognostic score based on serum CRP and albumin levels, has been implicated as a prognostic factor in NSCLC, inoperable gastroesophageal cancer and unresectable colorectal cancer.  In addition to the original GPS, the modified GPS (mGPS) was used to evaluate inflammatory status prior to surgery to determine, which score is more reflective of prognosis in patients with gastric cancer.  Jiang et al. showed that the mGPS can predict postoperative survival for patients with gastric cancer. More importantly, the mGPS can be achieved easily before operation, and it seems not inferior to conventional tumor markers like carcinoembryonic antigen and carbohydrate antigen 19-9.  However, whether the GPS and the mGPS have different prognostic value in each stage of the gastric cancer remains unclear.
Therefore, the present study overviews associated studies and comments on the value of the GPS/mGPS in patients with gastric cancer.
| > The Biological Basis of The Glasgow Prognostic Score/Modified Glasgow Prognostic Score and Its Value In Gastric Cancer|| |
Associated biological basis
Now it has become clearer that disease progression in cancer is dependent on a complex interaction of the characteristics of both the tumor and the host inflammatory response.  The presence of a systemic inflammatory response (SIR) is recognized to occur in the presence of malignancy, both in localized and metastatic disease. Alternatively, cancer continues to progress in a nonself-limiting manner while inducing their stroma, essential to growth, by activating the host's wound healing response. Thus, SIR associated with cancer must be ongoing and persistent.  However, it has not yet been established whether the presence of inflammation is related to inflammatory factors released by the tumor or due to impaired host immune response.  Although the exact mechanism by which systemic inflammation arises in cancer patients remains to be clarified, it is generally accepted that cancer associated inflammation is modulated by cancer cells, host stromal cells and their interactions.  So far, there has many studies on the mechanism of the inflammatory response in the procession of the disease, many of which focus on the relation of the inflammatory response and the immune. There is evidence suggest that the activation of the SIR is related to the compromised immune function and the increased activation of components of the innate immune system, such as the complement and macrophage function associated with revascularization of the tumor and blood-borne dissemination of cancer cells.  Therefore, people have realized that for the cancer patients, including the measurement of the SIR in the definition of cancer cachexia is of importance. Besides, in recently, it has become clearer that measurement of the SIR, compared with weight loss and performance status, are superior prognostic factors independent of tumor-related factors in advanced cancer. 
Crumley et al.  showed that the preoperative evaluation of SIR, as evidenced by an elevated CRP level, is important to the prognosis of patients with gastric cancer. Because advanced cancer is often associated with an inflammatory response, high CRP levels have been rather common in patients with advanced disease. CRP is synthesized predominantly in the liver, together with other acute-phase proteins. This process is induced in hepatocytes mainly by the pro-inflammatory cytokine, interleukin (IL)-6, which can be enhanced by IL-1b in an autocrine manner.  Besides, CRP is a nonspecific, but sensitive marker of SIR, as it exhibits no clinical variations with age or sex and is readily measured by standardized, reliable assays.  In previous reports, serum levels of albumin were associated with a poor therapeutic outcome in patients with colorectal cancer and hepatocyte cell carcinoma.  Besides, hypoalbuminemia is also recognized as part of the SIR.  Indeed, recent definitions of cancer cachexia include elevation of CRP and hypoalbuminemia.  It is recognized that the GPS composed of the CRP and albumin reflects both an ongoing SIR (CRP) and a progressive nutritional decline (albumin) in patients with advanced cancer.  The resultant prognostic score GPS (0, 1, 2) was first defined according to Forrest et al. in Glasgow  as follows: Patients with both an elevated CRP (>10 mg/l) and hypoalbuminemia (<35 g/l) were allocated a score of 2. Patients in whom only one of these biochemical abnormalities was present were allocated a score of 1. Patients in whom neither of these abnormalities was present were allocated a score of 0. On further investigation, the GPS was modified, termed the mGPS. The mGPS  allocated patients with an elevated CRP (>10 mg/l) a score of 1 or 2 depending on the absence or presence of hypoalbuminemia (<35 g/l), whereas patients showing no elevation in CRP (≤10 mg/l) were allocated a score of 0, even if hypoalbuminemia was present [Table 1].
| > The Value of The Glasgow Prognostic Score/Modified Glasgow Prognostic Score In Patients With Gastric Cancer|| |
A chronic SIR, as evidenced by the GPS/mGPS, has current and future clinical utility in a variety of cancer scenarios.  Until date, there are about 12 studies (exclusion of the studies of gastroesophageal cancer) reporting the value of the GPS/mGPS in gastric cancer [Table 2]. All studies showed that GPS/mGPS was associated with poor prognosis for patients with gastric cancer. Eight studies, comprising data on 3841 patients, reported prognostic value of the preoperative GPS/mGPS in patients undergoing resection of gastric cancer. Among of those, two studies compared the prognostic value of the GPS/mGPS with the cellular markers of the SIR including the NLR, platelet lymphocyte ratio (PLR) and showed that GPS/mGPS is superior to circulating white cellular components; one study reported that the preoperative mGPS were associated with poor prognosis in elderly rather than nonelderly patients with gastric cancer. Four studies reported that the GPS/mGPS could be a prognostic factor for advanced gastric cancer patients receiving palliative chemotherapy. One study showed that the nutritional status was associated with the GPS. In conclusion, there is increasing evidence that the GPS/mGPS predicted poor survival in patients with gastric cancer and associated with nutritional status.
|Table 2: Studies (n=11) of the prognostic value of the GPS/mGPS in patients with GC|
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The Comparison of The Glasgow Prognostic Score/Modified Glasgow Prognostic Score with The Common Prognostic Factors And The Comparison of The Glasgow Prognostic Score With Modified Glasgow Prognostic Score and Their Prognostic Values In Gastric Cancer In Each Stage
The comparison the value of the Glasgow Prognostic Score/modified Glasgow Prognostic Score with the common prognostic factors in gastric cancer
It is now increasingly recognized that disease progression in cancer and outcome of patients is not only dependent on the tumor-related factors but also host-related factors, in particular the SIR.  In the current clinical work, assessing the suitability of patients for treatment and predicting the prognosis are usually based on performance status, TNM stage, the ratio of positive to total lymph nodes, etc., However, as mentioned above, the widely accepted tumor-related prognostic factors are still needed to be further perfected. An inflammation based score, termed the GPS/mGPS composed of the CRP and albumin has prognostic value of survival, independent of tumor stage, ECOG-ps and treatment (active or palliative), has been shown in a variety of advanced common solid tumors.  GPS/mGPS not only represents some prognostic information of tumor biologic characteristics, but also is related to progressive functional and nutritional decline in patients and subsequent poor outcome. Besides, GPS/mGPS gives a preoperative risk assessment, whereas the lymph node ratio gives a postoperative risk assessment. Although an elevated preoperative GPS/mGPS would not preclude surgery, it would identify patients at high risk for recurrence and therefore would point to more careful tumor staging, follow-up and the need for neoadjuvant and/or adjuvant treatment.  For a comparison the value of the GPS/mGPS with the performance status, Forrest et al.'s study  showed that an inflammation-based prognostic score, the GPS, appeared to be superior to ECOG-ps in predicting the outcome following platinum-based chemotherapy. The result is similar to the study of Crumley et al.,  who reported that the presence of a SIR, as evidenced by the GPS, appears to be superior to the subjective assessment of ECOG-ps in predicting the response to platinum-based chemotherapy in patients with advanced gastroesophageal cancer. However, we should note that the number of the study is small, and only 28 patients in 68 patients had disease arising from the stomach. Therefore, whether the SIR, as evidenced by the GPS/mGPS, is superior to the subjective assessment of ECOG-ps, in predicting the prognosis and the response to chemotherapy in patients with gastric cancer still needs to explore in further studies.
There is increasing evidence that the inflammation seems to play a critical role in the development and progression of numerous cancers.  Several prognostic factors based on the SIR include the mGPS, the NLR, and the PLR, all of which have been reported to be independent predictors of survival in gastrointestinal cancer.  Contemporarily, it is not clear which of these scores best predicts survival in patients with gastric cancer. However, many recent studies indicate that preoperative or pretreatment GPS/mGPS was superior to the cellular components of the SIR in operable gastric cancer patients , and inoperable advanced or metastatic gastric cancer patients. , Similar results can find in colon cancer.  Further work is required to establish the superior prognostic value of the GPS/mGPS and whether together with traditional risk factors to better predict prognosis and individualize treatment strategies.
The comparison of the Glasgow Prognostic Score with modified Glasgow Prognostic Score and their prognostic values in gastric cancer in each stage
As for the definition of the GPS and mGPS, the decisive difference between GPS and mGPS is the inclusion of patients with hypoalbuminemia in the absence of an elevated CRP concentration. Hypoalbuminemia is due to malnutrition, which is a common feature of advanced cancer, so-called cachexia, and has been identified as an independent prognostic factor in patients with gastric cancer.  Therefore, part of the hypoalbumineima caused by the malnutrition may not represent the SIR. Conversely, CRP is a nonspecific but sensitive marker of SIR. Because advanced cancer is often associated with an inflammatory response, high CRP levels have been rather common in patients with advanced disease.  According to the previous concept that the development of hypoalbuminemia is often secondary to an ongoing SIR.  This consist with the result of Kubota et al.'s study  that only 49 (4.8%) patients had hypoalbuminemia in the absence of an elevated CRP concentration. Meantime, Crumley et al.  also showed a similar result that the relation between the hypoalbuminemia and poor cancer-specific survival is secondary to that of the SIR in patients with gastric cancer.
There are many studies discussing the prognostic value of GPS/mGPS in different stages of the gastric cancer. For the advanced gastric cancer, elevated GPS/mGPS was associated with reduced overall and disease-free survival. ,,,, Alternatively, for the relatively early-stage gastric cancer, it seems that the value of the GPS and that of the mGPS are different and fewer studies have compared the value of GPS with mGPS. Jiang et al.  showed survival differences depending on the mGPS in patients with relatively early-stage gastric cancer. However, as showed in that study, the rate of mGPS 2 in patients with stage I gastric cancer was so low that it is too early to give a definite conclusion. In another study, Kubota et al.  compared and showed a more clearer result that GPS reflected survival more accurately than mGPS in the prognosis of patients with gastric cancer surgery. In that study, the survival curves of mGPS 0 and 1 overlapped. Whereas, there were some differences in survival among GPS 0, 1, and 2 patients. However, a remarkable feature of this study was that more than half of the patients were T1N0 and p stage I and underwent laparoscopic surgery for early gastric cancer rather than including all stages or advanced gastric cancer. Consequently, it seems that for the relatively early-stage gastric cancer, the prognostic value of the GPS overweights that of the mGPS. More studies are needed to draw a definitive conclusion.
Therefore, it seems that choosing GPS or mGPS as the prognostic factor for gastric cancer in a different stage will contribute to a different result. In a clinical study, the score of 1 was most commonly found to be a result of an elevated CRP, emphasizing the inflammatory basis of the GPS.
Consequently, a directive difference is that patients with a CRP (<10 mg/l) and hypoalbuminemia (>35 g/l) were allocated a score of 1 based on the GPS scale, but a score of 0 based on the mGPS scale, which contribute to misleading treatment choices and different prognosis. Therefore, we raise a question that whether the mGPS reflects survival more accurately than GPS in the prognosis of patients with advanced gastric cancer and for the relatively early-stage gastric cancer the mGPS reflects survival more accurately than GPS. Further studies are still needed to explore and answer the question.
| > Clinical Application Of The Systemic Inflammation Based Score Glasgow Prognostic Score/Modified Glasgow Prognostic Score In Patients With Gastric Cancer|| |
Although advanced gastric cancer has a very poor prognosis and survival, there is marked heterogeneity in the duration of survival among patients. Therefore, there have been increasing efforts to investigate the prognostic factors related to survival. As we discussed above, the widely used prognostic factors in clinical work, such as ECOG-ps, TNM stage, the ratio of positive to total lymph nodes, are available only depending on postoperative histological specimen, and some are recognized to be subjective. An inflammation-based prognostic score, Glasgow Prognostic Score, GPS/mGPS is a tumor stage-and treatment-independent, routinely preoperative or pretreatment available and well-standardized prognostic factor, had independent prognostic value in lung, breast, esophageal, gastric, gastroesophageal, colorectal, pancreas, hepatocellular, renal, cervical cancer.  Therefore, to better predict the prognosis of patients with gastric cancer, GPS/mGPS should be included together with the tumor stage and ECOG-ps, etc., in the routine clinical assessment.
For patients with advanced inoperable cancer, the appropriate selection of patients, most likely to benefit is of considerable importance. The decision whether to offer active or palliation treatment is based on a number of factors including an assessment of patient performance status. However, the assessment of performance status is subjective, and it reflects functional status at a specific point in time. Thus, the development of more objective assessment factors through a laboratory-based scoring system remains appealing. By contrast, the GPS, based on the presence of ongoing SIR and hypoalbuminemia, is routinely available and well standardized and reflects the process that drives the progressive nutritional decline of the patient with advanced cancer. Just as Crumley et al.  showed that patients with stage III/IV gastroesophageal cancer receiving active treatment, there was approximately a five-fold decrease in the survival rate between those patients with a GPS of 0 (57%) and those with a GPS of 2 (12%), which suggests that those patients derive little survival benefit from active treatment.
More recently, it has been reported that cytochrome P450 3A activity, the principal drug metabolizing enzyme in a variety of chemotherapeutic agents, is compromised in advanced lung cancer patients with an elevated CRP concentration.  Platinum is one of important chemotherapeutics for gastric cancer. This suggests that the presence of a SIR may be an important factor in determining the ability of gastric cancer patients to tolerate platinum-based chemotherapy. The result was reported in Crumley et al.'s study  that in comparison with patients with a GPS of 0 gastroesophageal cancer, those patients with a GPS of 1 or 2 required more frequent chemotherapy dose reduction (P < 0.05), were less likely to exhibit a clinical response to treatment (P < 0.05), and had shorter survival (P < 0.05), the GPS, appeared to be superior to the clinician assessment of performance status. Thus, the GPS may aid at the selection of patients with gastric cancer who tolerate platinum-based chemotherapy and predict the efficacy of chemotherapy in the future.
The GPS/mGPS, composed of CRP based on the presence of ongoing SIR and hypoalbuminemia, has independent prognostic value in patients with gastric cancer, aids at deciding active or palliation treatment, selecting patients with gastric cancer who tolerate platinum-based chemotherapy and predicting the efficacy of chemotherapy. If this were shown to be the case, it would also be an important tip for clinicians to determine whether normalization of the GPS/mGPS, anti-inflammatory agents (e.g. steroids, nonsteroidal anti-inflammatory drugs) and the maintenance of performance status or nutritional status are needed in clinical work.
| > Conclusions|| |
From the present review, we can conclude that the GPS/mGPS, independent of age, stage, performance status, weight-loss and hypoalbuminemia, has the prognostic value of survival for the patients with gastric cancer, aids at deciding active or palliation treatment and is helpful to select patients who tolerate platinum-based chemotherapy. For the future perspective, just as Roxburgh et al.  showed that an example of how such information might be used clinically would be to either delay adjuvant treatment until an improvement in inflammatory status or to use anti-inflammatory treatment to normalize inflammatory status. If such treatment is successful then, the anti-inflammatory treatment can go forward to a randomized controlled trial. Another area of future interest, given the importance of inflammation in tumor progression, is the use of inflammation-based prognostic scores in early-stage disease identified by screening.
However, a comparison and selection of the GPS/mGPS in different stages of gastric cancer are less discussed and not established. In addition, whether the GPS/mGPS is superior to the subjective assessment of ECOG-ps, TNM stage or not in predicting prognosis and the response to chemotherapy in patients with gastric cancer is still needed to explore in further studies. Besides, the GPS/mGPS can combine with the common prognostic factors such as the ECOG-ps, TNM stage, the ratio of positive to total lymph nodes to improve the value of the prognostic value of survival. Therefore, GPS based on abnormalities of serum albumin and CRP, can thus reflect both the presence of a SIR and the progressive nutritional decline of the patient with advanced cancer and should be reasonable as a universal parameter to determine prognosis of patients with gastric carcinoma. Probably at most institutions, this quite useful and simple parameter might be clinically used to predict prognosis of patients with gastric carcinoma, accurate patient stratification, improve clinical decision making and possibly contribute to more rational study design and analysis.
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[Table 1], [Table 2]