Donald C. McMillan

Role of systemic inflammatory response in predicting survival in patients with primary operable cancer

Disease progression in cancer is dependent on the complex interaction between the tumor and the host inflammatory response. There is substantial evidence in advanced cancer that host factors, such as weight loss, poor performance status and the host systemic inflammatory response, are linked, and the latter is an important tumor-stage-independent predictor of outcome. Indeed, the systemic inflammatory response, as evidenced by an elevated level of C-reactive protein, is now included in the definition of cancer cachexia. This review examines the role of the systemic inflammatory response in predicting survival in patients with primary operable cancer. Approximately 80 studies have evaluated the role of the systemic inflammatory response using biochemical or hematological markers, such as elevated C-reactive protein levels, hypoalbuminemia or increased white cell, neutrophil and platelet counts. Combinations of such factors have been used to derive simple inflammation-based prognostic scores, such as the Glasgow Prognostic Score, the neutrophil:lymphocyte ratio and the platelet:lymphocyte ratio. This review demonstrates that there is now good evidence that preoperative measures of the systemic inflammatory response predict cancer survival, independent of tumor stage, in primary operable cancer. The evidence is particularly robust in colorectal (including liver metastases), gastro-esophageal and renal cancers. As described in this article, measurement of the systemic inflammatory response is simple, reliable and can be clinically incorporated into current staging algorithms. This will provide the clinician with a better prediction of outcome, and therefore better treatment allocation in patients with primary operable cancer. Furthermore, systemic inflammation-based markers and prognostic scores not only identify patients at risk, but also provide well-defined therapeutic targets for future clinical trials.

The systemic inflammation-based Glasgow Prognostic Score: A decade of experience in patients with cancer

Since the initial work, a decade ago that the combination of C-reactive protein and albumin, the Glasgow Prognostic Score (GPS), had independent prognostic value in patients with cancer, there have been more than 60 studies (>30,000 patients) that have examined and validated the use of the GPS or the modified GPS (mGPS) in a variety of cancer scenarios. The present review provides a concise overview of these studies and comments on the current and future clinical utility of this simple objective systemic inflammation-based score. The GPS/mGPS had independent prognostic value in (a) unselected cohorts (4 studies, >19,400 patients) (b) operable disease (28 studies, >8,000 patients) (c) chemo/radiotherapy (11 studies, >1500 patients) (d) inoperable disease (11 studies, >2,000 patients). Association studies (15 studies, >2,000 patients) pointed to an increased GPS/mGPS being associated with increased weight and muscle loss, poor performance status, increased comorbidity, increased pro-inflammatory and angiogenic cytokines and complications on treatment. These studies have originated from 13 different countries, in particular the UK and Japan. A chronic systemic inflammatory response, as evidenced by the GPS/mGPS, is clearly implicated in the prognosis of patients with cancer in a variety of clinical scenarios. The GPS/mGPS is the most extensively validated of the systemic inflammation-based prognostic scores and therefore may be used in the routine clinical assessment of patients with cancer. It not only identifies patients at risk but also provides a well defined therapeutic target for future clinical trials. It remains to be determined whether the GPS has prognostic value in other disease states.

The systemic inflammation-based neutrophil–lymphocyte ratio: Experience in patients with cancer

There is increasing and consistent evidence that cancer-associated inflammation is a key determinant of outcome in patients with cancer. Various markers of inflammation have been examined over the past decade in an attempt to refine stratification of patients to treatment and predict survival. One routinely available marker of the systemic inflammatory response is the neutrophil-lymphocyte ratio (NLR), which is derived from the absolute neutrophil and absolute lymphocyte counts of a full blood count. To date, over 60 studies (>37,000 patients) have examined the clinical utility of the NLR to predict patient outcomes in a variety of cancers. The present systematic review examines and comments on the clinical utility of the NLR. The NLR had independent prognostic value in (a) unselected cohorts (1 study of >12,000 patients), (b) operable disease (20 studies, >4000 patients), (c) patients receiving neoadjuvant treatment and resection (5 studies, >1000 patients), (d) patients receiving chemo/radiotherapy (12 studies, >2000 patients) and (e) patients with inoperable disease (6 studies, >1200 patients). These studies originated from ten different countries, in particular UK, Japan, and China. Further, correlative studies (15 studies, >8500 patients) have shown that NLR is elevated in patients with more advanced or aggressive disease evidenced by increased tumour stage, nodal stage, number of metastatic lesions and as such these patients may represent a particularly high-risk patient population. Further studies investigating the tumour and host-derived factors regulating the systemic inflammatory response, in particular the NLR, may identify novel treatment strategies for patients with cancer.

Systemic inflammation, nutritional status and survival in patients with cancer.

Purpose of reviewThere is now good evidence in humans that a chronic systemic inflammatory response results in the cardinal features of cancer cachexia, principally the progressive loss of weight (in particular lean tissue). This review examines the role of recent simple objective systemic inflammation-based scores in predicting reduction of nutritional status and survival. Recent findingsThe most common measure of the systemic inflammatory response in cancer patients has been an elevated C-reactive protein concentration. This has now been included in recent definitions of cancer cachexia. There are also recent systemic inflammation-based scores, the Glasgow Prognostic Score, Neutrophil Lymphocyte Ratio and the Platelet Lymphocyte Ratio that have been shown to have prognostic value in cancer patients. These scores, in particular the Glasgow Prognostic Score, enable identification of patients who are, or likely, to develop cachexia, have a poor response to treatment and who are likely to have poor survival. SummaryA chronic systemic inflammatory response is clearly implicated in the progressive nutritional and functional decline in the cancer patients and their subsequent poor outcome. Systemic inflammation-based prognostic scores not only identify patients at risk but also provide well defined therapeutic targets for future clinical trials targeting nutritional decline.

Systemic inflammatory response predicts survival following curative resection of colorectal cancer

Some studies have shown that the presence of a systemic inflammatory response, as evidenced by raised circulating concentrations of C‐reactive protein (CRP), predicted recurrence and overall survival in patients with colorectal cancer. The aim of this study was to examine the relationship between the inflammatory response and overall and cancer‐specific survival in patients undergoing potentially curative resection for colorectal cancer.

A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study

INTRODUCTION Components of the systemic inflammatory response, combined to form inflammation-based prognostic scores (modified Glasgow Prognostic Score (mGPS), Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Prognostic Index (PI), Prognostic Nutritional Index (PNI)) have been associated with cancer specific survival. The aim of the present study was to compare the prognostic value of these scores. METHODS Patients (n=27,031) who had an incidental blood sample taken between 2000 and 2007 for C-reactive protein, albumin, white cell, neutrophil, lymphocyte and platelet counts, as well as a diagnosis of cancer (Scottish Cancer Registry) were identified. Of this group 8759 patients who had been sampled within two years following their cancer diagnosis were studied. RESULTS On follow up, there were 5163 deaths of which 4417 (86%) were cancer deaths. The median time from blood sampling to diagnosis was 1.7 months. An elevated mGPS, NLR, PLR, PI and PNI were predictive of a reduced cancer specific survival independent of age, sex and deprivation and tumour site (all p<0.001). The area under the receiver operator curves was greatest for mGPS and PI. Specifically, in colorectal cancer, an elevated mGPS and PI were predictive of a reduced cancer specific survival independent of age, sex, deprivation and tumour stage (both p<0.001). CONCLUSION The results of the present study show that systemic inflammation-based scores, in particular the mGPS and PI, have prognostic value in cancer independent of tumour site. Based on the present results and the existing validation literature, the mGPS should be included in the routine assessment of all patients with cancer.

Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer

A score based on the combination of the systemic inflammatory response and albumin hazards ratio (HR) 1.70, 95% CI 1.23 – 2.35, P=0.001) was comparable in prognostic value to that based on stage and performance status (HR 1.48, 95% CI 1.12 – 1.95, P=0.006) in patients with inoperable non-small-cell lung cancer. The former is simple to measure and well standardised.

Impact of anastomotic leakage on long-term survival of patients undergoing curative resection for colorectal cancer

The impact of anastomotic leakage on immediate postoperative mortality in patients undergoing potentially curative resection for colorectal cancer is well recognized. Its impact on long‐term survival is less clear. The aim of the present study was to evaluate the relationship between anastomotic leakage and long‐term survival in patients undergoing potentially curative resection for colorectal cancer.

Evaluation of an inflammation-based prognostic score (GPS) in patients with metastatic breast cancer

Prediction of outcome in patients with metastatic breast cancer remains problematical. The present study evaluated the value of an inflammation-based score (Glasgow Prognostic Score, GPS) in patients with metastatic breast cancer. The GPS was constructed as follows: patients with both an elevated C-reactive protein (>10 mg l−1) and hypoalbuminaemia (<35 g l−1) were allocated a score of 2. Patients in whom only one or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively. In total, 96 patients were studied. During follow-up 51 patients died of their cancer. On multivariate analysis of the GPS and treatment received, only the GPS (HR 2.26, 95% CI 1.45–3.52, P<0.001) remained significantly associated with cancer-specific survival. The presence of a systemic inflammatory response (the GPS) appears to be a useful indicator of poor outcome independent of treatment in patients with metastatic breast cancer.

An inflammation-based prognostic score and its role in the nutrition-based management of patients with cancer

Progressive involuntary weight loss, in particular the loss of lean tissue, is common in patients with advanced cancer and has long been recognised to result in a deterioration in performance status and quality of life, increased morbidity and mortality. The aetiology of such weight loss or cachexia is complex and involves both tumour and host responses. Thus, identification of patients who are or are likely to become cachectic has been problematic. In addition to a reduction in appetite and increased satiety leading to poor dietary intake, there is now increasing clinical evidence that the activation of a chronic ongoing systemic inflammatory response is one of the earliest and most important contributory factors to cachexia. Such findings help to explain the failure of simple nutritional programmes to reverse weight loss adequately in patients with cancer. In the present paper the development of an inflammation-based score is described, which is derived from the acute-phase proteins C-reactive protein and albumin and is termed the Glasgow prognostic score (GPS). Its value as a predictor of survival, independent of tumour stage, performance status and treatment (active or palliative), has been shown in a variety of advanced common solid tumours. The nature of the relationship between the GPS, appetite, body composition, performance status and quality of life of the patient with advanced cancer will be described. Recently, it has become evident that the systemic inflammatory response is also present in a smaller proportion of patients with primary operable cancer and is also predictive of disease progression and poor survival. The role of GPS in clinical decision making will be discussed.