Campbell S. Roxburgh

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 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.

Comparison of the Prognostic Value of Inflammation-Based Pathologic and Biochemical Criteria in Patients Undergoing Potentially Curative Resection for Colorectal Cancer

Objective:To examine interrelationships between the local inflammatory response (Klintrup and Jass scores) and the systemic inflammatory response (Glasgow prognostic score [GPS]), and compare their prognostic value in patients undergoing curative resection for colorectal cancer. Background:Both localized peritumoral inflammatory cell infiltrate and the host systemic inflammatory response are known to have prognostic value in colorectal cancer. However, the interrelationships of biochemical and cellular components of the systemic inflammatory response and the local inflammatory response are poorly understood. Methods:Retrospective study of 287 patients who underwent surgery between 1997 and 2004. Data were collected from routine preoperative blood tests. Routine pathology specimens were scored according to Jass and Klintrup criteria for peritumoral infiltrate. Results:Increased Dukes stage was associated with less peritumoral infiltrate (Jass criteria: P < 0.001, Klintrup criteria: P < 0.01). Increased modified GPS (mGPS) was associated with increased circulating white cell (P < 0.01) and neutrophil (P < 0.01) counts and low lymphocyte counts (P < 0.01). Increased circulating white cell count was associated with increased neutrophil count (P < 0.001) and low-grade peritumoral infiltrate (P < 0.05, Klintrup criteria). Jass and Klintrup criteria for peritumoral infiltrate were directly associated (P < 0.001). On univariate survival analysis of patients with node-negative disease (Dukes A and B), age (P < 0.01), mGPS (P < 0.01), neutrophil count (P < 0.05), and Klintrup criteria (P < 0.05) were associated with cancer-specific survival. On multivariate survival analysis in node-negative disease, the mGPS (hazard ratio: 2.61, 95% CI: 1.27–5.35, P < 0.01) and Klintrup criteria (hazard ratio: 6.31, 95% CI: 1.40–28.44, P < 0.05) were independently associated with cancer-specific survival. Conclusions:The results of the present study suggest low peritumoral infiltrate (Klintrup criteria) and increased systemic inflammation (mGPS criteria) are linked through the cell-mediated immune system. Furthermore, both pathologic (Klintrup) and biochemical (mGPS) measures of the inflammatory response predict survival after colorectal cancer surgery.

Cancer and systemic inflammation: treat the tumour and treat the host

Determinants of cancer progression and survival are multifactorial and host responses are increasingly appreciated to have a major role. Indeed, the development and maintenance of a systemic inflammatory response has been consistently observed to confer poorer outcome, in both early and advanced stage disease. For patients, cancer-associated symptoms are of particular importance resulting in a marked impact on day-to-day quality of life and are also associated with poorer outcome. These symptoms are now recognised to cluster with one another with anorexia, weight loss and physical function forming a recognised cluster whereas fatigue, pain and depression forming another. Importantly, it has become apparent that these symptom clusters are associated with presence of a systemic inflammatory response in the patient with cancer. Given the understanding of the above, there is now a need to intervene to moderate systemic inflammatory responses, where present. In this context the rationale for therapeutic intervention using nonselective anti-inflammatory agents is clear and compelling and likely to become a part of routine clinical practice in the near future. The published literature on therapeutic intervention using anti-inflammatory agents for cancer-associated symptoms was reviewed. There are important parallels with the development of useful treatments for the systemic inflammatory response in patients with rheumatological disease and cardiovascular disease.

The role of the in situ local inflammatory response in predicting recurrence and survival in patients with primary operable colorectal cancer

Colorectal cancer progression and survival is dependent on complex interactions between the tumour and the host. The pronounced local inflammatory response in and around the tumour is thought to represent the in situ host anti-tumour immune response. Since early reports, 40 years ago, there has been a continuing interest in establishing the cellular composition of immune cell infiltrates and their relationship with survival in colorectal cancer. In this review, we comprehensively examine the evidence for the local inflammatory cell reaction/in situ immune response in predicting outcome in primary operable colorectal cancer and make recommendations as to how such information may be incorporated into routine clinical assessment. Generally, an increasing number/density of immune cells in and around the tumour is associated with improved outcome in over 100 studies. Whilst the prognostic value of a generalized lymphocytic infiltrate or non-specific peritumoural inflammatory response is strongly related to survival based on 40 different studies, it is also apparent that most individual immune cell types relate to recurrence and cancer specific survival. The evidence is particularly robust for tumour infiltrating T lymphocytes and their subsets (CD3+, CD8+, CD45RO+, FOXP3+) in addition to tumour associated macrophages, dendritic cells and neutrophils. Taken together, the evidence suggests both adaptive and innate anti-tumour immune responses play key roles in determining cancer progression. In order to establish routine clinical utility there is a need to rationalise this prognostic information, published over a 40 years period, into a standardized assessment of tumour inflammatory cell infiltrate. Such standardization may also guide development of novel therapeutic interventions.

The Relationships between Body Composition and the Systemic Inflammatory Response in Patients with Primary Operable Colorectal Cancer

Background Weight loss is recognised as a marker of poor prognosis in patients with cancer but the aetiology of cancer cachexia remains unclear. The aim of the present study was to examine the relationships between CT measured parameters of body composition and the systemic inflammatory response in patients with primary operable colorectal cancer. Patient and Methods 174 patients with primary operable colorectal cancer who underwent resection with curative intent (2003–2010). Image analysis of CT scans was used to measure total fat index (cm2/m2), subcutaneous fat index (cm2/m2), visceral fat index (cm2/m2) and skeletal muscle index (cm2/m2). Systemic inflammatory response was measured by serum white cell count (WCC), neutrophil:lymphocyte ratio (NLR) and the Glasgow Prognostic Score (mGPS). Results There were no relationships between any parameter of body composition and serum WCC or NLR. There was a significant relationship between low skeletal muscle index and an elevated systemic inflammatory response, as measured by the mGPS (p = 0.001). This was confirmed by linear relationships between skeletal muscle index and both C-reactive protein (r = −0.21, p = 0.005) and albumin (r = 0.31, p<0.001). There was no association between skeletal muscle index and tumour stage. Conclusions The present study highlights a direct relationship between low levels of skeletal muscle and the presence of a systemic inflammatory response in patients with primary operable colorectal cancer.

The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer

BACKGROUND Tumour stroma percentage (TSP) has previously been reported to predict survival in patients with colorectal cancer (CRC); however, whether this is independent of other aspects of the tumour microenvironment is unknown. In the present study, the relationship between TSP, the tumour microenvironment and survival was examined in patients undergoing elective, curative CRC resection. PATIENTS AND METHODS Patients undergoing resection at a single centre (1997-2008) were identified from a prospective database. TSP was measured at the invasive margin and its association with cancer-specific survival (CSS) and clinicopathological characteristics examined. RESULTS Three hundred and thirty-one patients were included in the analysis. TSP was associated with CSS in patients with stage I-III disease [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.17-2.92, P = 0.009], independent of age, systemic inflammation, N stage, venous invasion and Klintrup-Mäkinen score. Furthermore, TSP was associated with reduced CSS in patients with node-negative disease (HR 2.14, 95% CI 1.01-4.54, P = 0.048) and those who received adjuvant chemotherapy (HR 2.83, 95% CI 1.23-6.53, P = 0.015), independent of venous invasion and host inflammatory responses. TSP was associated with several adverse pathological characteristics, including advanced T and N stage. Furthermore, TSP was associated with an infiltrative invasive margin and inversely associated with necrosis. CONCLUSIONS The TSP was a significant predictor of survival in patients undergoing elective, curative CRC resection, independent of adverse pathological characteristics and host inflammatory responses. In addition, TSP was strongly associated with local tumour growth and invasion.BACKGROUND Tumour stroma percentage (TSP) has previously been reported to predict survival in patients with colorectal cancer (CRC); however, whether this is independent of other aspects of the tumour microenvironment is unknown. In the present study, the relationship between TSP, the tumour microenvironment and survival was examined in patients undergoing elective, curative CRC resection. PATIENTS AND METHODS Patients undergoing resection at a single centre (1997-2008) were identified from a prospective database. TSP was measured at the invasive margin and its association with cancer-specific survival (CSS) and clinicopathological characteristics examined. RESULTS Three hundred and thirty-one patients were included in the analysis. TSP was associated with CSS in patients with stage I-III disease [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.17-2.92, P = 0.009], independent of age, systemic inflammation, N stage, venous invasion and Klintrup-Mäkinen score. Furthermore, TSP was associated with reduced CSS in patients with node-negative disease (HR 2.14, 95% CI 1.01-4.54, P = 0.048) and those who received adjuvant chemotherapy (HR 2.83, 95% CI 1.23-6.53, P = 0.015), independent of venous invasion and host inflammatory responses. TSP was associated with several adverse pathological characteristics, including advanced T and N stage. Furthermore, TSP was associated with an infiltrative invasive margin and inversely associated with necrosis. CONCLUSIONS The TSP was a significant predictor of survival in patients undergoing elective, curative CRC resection, independent of adverse pathological characteristics and host inflammatory responses. In addition, TSP was strongly associated with local tumour growth and invasion.

Comparison of tumour-based (Petersen Index) and inflammation-based (Glasgow Prognostic Score) scoring systems in patients undergoing curative resection for colon cancer

After resection, it is important to identify colon cancer patients, who are at a high risk of recurrence and who may benefit from adjuvant treatment. The Petersen Index (PI), a prognostic model based on pathological criteria is validated in Dukes’ B and C disease. Similarly, the modified Glasgow Prognostic Score (mGPS) based on biochemical criteria has also been validated. This study compares both the scores in patients undergoing curative resection of colon cancer. A total of 244 patients underwent elective resection between 1997 and 2005. The PI was constructed from pathological reports; the mGPS was measured pre-operatively. The median follow-up was 67 months (minimum 36 months) during which 109 patients died; 68 of them from cancer. On multivariate analysis of age, Dukes’ stage, PI and mGPS, age (hazard ratio, HR, 1.74, P=0.001), Dukes’ stage (HR, 3.63, P<0.001), PI (HR, 2.05, P=0.010) and mGPS (HR, 2.34, P<0.001) were associated independently with cancer-specific survival. Three-year cancer-specific survival rates for Dukes’ B patients with the low-risk PI were 98, 92 and 82% for the mGPS of 0, 1 and 2, respectively (P<0.05). The high-risk PI population is small, in particular for Dukes’ B disease (9%). The mGPS further stratifies those patients classified as low risk by the PI. Combining both the scoring systems could identify patients who have undergone curative surgery but are at high-risk of cancer-related death, therefore guiding management and trial stratification.

Prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer.

Tumour necrosis is a marker of poor prognosis in some tumours but the mechanism is unclear. This study examined the prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer.

Does interleukin-6 link explain the link between tumour necrosis, local and systemic inflammatory responses and outcome in patients with colorectal cancer?

Cancer-associated inflammation has been identified as a key determinant of disease progression and survival in colorectal cancer. In particular, it has been consistently reported that both the local and systemic inflammatory responses play an important role in determining outcome in colorectal cancer. Given the importance of cancer-associated inflammation, up-regulation or attenuation of these respective inflammatory responses may be important for progression and survival in colorectal cancer. Recent work has focused on the inter-relationships between the tumour and these key inflammatory processes. In particular, tumour necrosis has been reported to be associated with decreased local inflammatory infiltrate and with elevated markers of systemic inflammation in colorectal cancer and has been proposed as a potential link between the systemic and local inflammatory responses. Thus there is increasing interest in the potential biochemical mediators of this link. In this review we examine the evidence for IL-6 in the natural history of colorectal cancer and its relationship with tumour necrosis and the local and systemic inflammatory responses. There is now good evidence that tumour concentrations of IL-6 have been directly associated with increased necrosis, proliferation, differentiation and vascular invasion, while circulating concentrations of IL-6 are directly associated with T-stage, CRP concentrations and poorer survival. Also, interleukin-6 and down-stream pathways, such as the JAK/STAT pathway, have emerged as important factors in the modulation of cancer-associated inflammation. Therefore, IL-6 has emerged as a key mediator of the relationship between tumour necrosis, local and systemic inflammatory responses and outcome in patients with colorectal cancer.