title: An investigation of the relationship between the systemic inflammatory response, body composition and outcomes in patients with cancer
Creators: name: Ross, Dolan
Publisher: name: University of Glasgow
Year: 2020
Subjects: subject: Systemic inflammation, body composition, tumour metabolic activity, survival.

description: Globally cancer remains one of the leading causes of mortality. Overall, it has been esti-mated that one in three people will develop can¬cer in their lifetime, and one in four will die from it. While a curative intent will always be the aim of any surgical or oncological treatment a significant proportion of patients will go on to develop locally advanced or metastatic disease. Patient outcomes are not solely determined by host or tumour factors but rather by a complex interaction of both. Indeed, the systemic changes associated with cancer including reduced appetite, weight loss and poorer performance can significantly impact on both the quality and quantity of life in patients with cancer. As a result, accurate and realistic prognostication is vitally important and can guide clinical decision making. In its simplest form the systemic inflammatory response is a reaction to tissue injury brought on by ischaemia, necrosis, trauma, hypoxia or cancer. It is increasingly clear that cancer progression and outcomes are dependent on a complex interaction between both tumour and host characteristics including the systemic inflammatory response. Clinically, the commonest means of measuring the systemic inflammatory response in patients with cancer is with the use of biochemical or haematological markers. In practice this means an elevated C-reactive protein (CRP), hypoalbuminaemia or increased white cells (WCC), neutrophil and platelet counts. The work presented in this thesis further examines the relationship between the systemic inflammatory response, body composition, tumour metabolic activity and outcomes in patients with cancer. The effect of the systemic inflammatory response on outcomes in patients with cancer was examined directly. The relationship between the systemic inflammatory response and changes in body composition and their relationship to outcomes was then examined with cross-sectional and longitudinal studies. Finally, the question of the driving force behind the relationship between the systemic inflammatory response and changes in body composition was examined by looking at tumour metabolic activity in patients with cancer. The results of the two large meta-analyses in both operable and advanced cancers can be seen in Chapter 3 and 4. In operable cancer the systemic inflammatory response had independent prognostic value, across tumour types and geographical locations. On meta-analysis there was a significant relationship between an elevated Neutrophil Lymphocyte Ratio (NLR) and both overall (p&lt;0.00001) and cancer specific survival (p&lt;0.00001), between an elevated Lymphocyte Monocyte Ratio (LMR) and both overall (p&lt;0.00001) and cancer specific survival (p&lt;0.00001), between an elevated Platelet Lymphocyte Ratio (PLR) and both overall (p&lt;0.00001) and cancer specific survival (p=0.005) and between an elevated Glasgow Prognostic Score (GPS)/modified Glasgow Prognostic Score (mGPS) and both overall (p&lt;0.00001) and cancer specific survival (p&lt;0.00001). In advanced cancer the systemic inflammatory response also had prognostic value, across tumour types and geographical locations. On meta-analysis there was a significant relationship between an elevated NLR and both overall survival (p&lt;0.00001) and cancer specific survival (CSS) (p&lt;0.00001), between an elevated PLR and overall survival (p=0.0003) and between an elevated GPS/mGPS and both overall (p&lt;0.00001) and cancer specific survival (p=0.0001). The majority of studies in these two meta-analyses were retrospective in nature, however the results of a further large systematic review focusing solely on randomised control trials can be seen in Chapter 5. In this review the GPS/mGPS was shown to have prognostic value in Non-Small Cell Lung Cancer (NSCLC), oesophageal cancer, pancreatic cancer, prostate cancer and breast cancer. While the NLR was shown to have prognostic value in nasopharyngeal cancer, oesophageal cancer, pancreatic cancer, biliary cancer, prostate cancer and multiple cancer types. Therefore, the prognostic strength of the systemic inflammatory response has been confirmed across over 400 papers including 36 prospective randomised control trials. However, the question still remained about the level of systemic inflammation in cancer patients as a whole. In order to answer this a further systematic review was undertaken in Chapter 6. This examined the prevalence of cancer associated systemic inflammation as measured by the GPS/mGPS and its implications for the ongoing care of patients with cancer. In this review which contained 140 studies including 40,893 patients the percentage of patients who were systemically inflamed varied from 28% to 63% according to tumour type. The most commonly studied cancer overall was colorectal cancer in which 40% of patients were systemically inflamed. In operable disease the percentage of patients who were systemically inflamed varied from 21% to 38% in gastroesophageal and colorectal cancer respectively. Again, the most commonly studied cancer was colorectal cancer and 38% were systemically inflamed. In inoperable disease the percentage of patients who were systemically inflamed varied from 29% to 79% in prostate and haematological cancers respectively. This confirmed that the systemic inflammatory response was common in both operable and inoperable cancers and could prove to be a fruitful target for therapeutic interventions in the future. The results of Chapter 3-5 show that the two most widely validated methods of monitoring the systemic inflammatory response are the GPS/mGPS and NLR. These are considered to be cumulative scores and composite ratios respectively. The results of Chapter 7 focuses on comparing the prognostic value of both cumulative scores and composite ratios in patients undergoing surgery for colon cancer (n=801). When adjusted for Tumour Node Metastasis (TNM) stage, NLR&gt;5 (p&lt;0.001), Neutrophil Lymphocyte Score (NLS, p&lt;0.01), Platelet Lymphocyte Score (PLS, p&lt;0.001), LMR&lt;2.4 (p&lt;0.001), Lymphocyte Monocyte Score (LMS, p&lt;0.001), Neutrophil Platelet Score (NPS, p&lt;0.001), CRP Albumin Ratio (CAR, p&lt;0.001) and mGPS (p&lt;0.001) were significantly associated with cancer specific survival. In patients undergoing elective surgery (n=689) the majority of the composite ratios/scores correlated with age (p&lt;0.01), BMI (p&lt;0.01), T-stage (p&lt;0.01), venous invasion (p&lt;0.01) and peritoneal involvement (p&lt;0.01). When NPS (myeloid) and mGPS (liver) were directly compared their relationship with both overall and cancer specific survival was similar. These results suggest that both composite ratios and cumulative scores had prognostic value, independent of TNM stage, in patients with colon cancer. However, cumulative scores, based on normal reference ranges, were simpler and more consistent for clinical use. The importance of the relationship between the systemic inflammatory response and changes in physical function have long been reported particularly in the setting of patients with advanced cancer. This relationship was examined further in Chapter 8 which was a post hoc analysis of a previously completed randomised control trial assessing the effect of corticosteroid use on analgesic requirements in patients with advanced disease (n=40). It showed that patients with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2 and an mGPS of 2 had a higher Interleukin-6 (IL-6, p=0.017) level and poorer overall survival (p&lt;0.001) when compared to patients with an ECOG-PS of 0/1 and an mGPS of 0. This work provides supporting evidence for the potential therapeutic targeting of IL-6 in patients with advanced cancer which is currently being explored with the use of immunomodulatory agents such as tocilizumab. These results suggest that there is considerable merit in combining monitoring of the systemic inflammatory response using acute phase proteins and other factors such as performance status in patients with cancer. Indeed this method of prognostication is given greater weight by the results of Chapter 10 which show in 730 patients with advanced cancer that on multivariate cox regression analysis ECOG-PS (HR 1.61 95%CI 1.42-1.83, p&lt;0.001), mGPS (HR 1.53, 95%CI 1.39-1.69, p&lt;0.001) and Body mass index/Weight Loss (BMI/WL) grade (HR 1.41, 95%CI 1.25-1.60, p&lt;0.001) remained independently associated with overall survival. In patients with a BMI/WL grade 0/1 both ECOG and mGPS remained independently associated with overall survival. This further suggests that the ECOG/mGPS framework may form the basis of risk stratification of survival in patients with advanced cancer. The use of CT scanning to determine the quantity and quality of skeletal muscle in patients with cancer is an increasing area of research and clinical interest. The two most commonly used software packages for image analysis are ImageJ and Slice-O-Matic. In Chapter 2 the differential impact of the use of these software packages is examined in patients undergoing surgery for colorectal cancer (n=341). In this study, Bland-Altman analysis showed that ImageJ gave consistently higher values for all body composition parameters (p&lt;0.001), resulting in more patients classified as having a high subcutaneous fat index (SFI, p&lt;0.001) and visceral fat index (VFI, p&lt;0.001) and fewer patients being classified as having a low skeletal muscle index (SMI, p&lt;.0001) and skeletal muscle density (SMD, p&lt;0.001). In addition, SFI, VFI, SMI and SMD were significantly associated with shorter overall survival when calculated with ImageJ (all p&lt;0.05). These results suggest that with the drive towards the incorporation of CT derived body composition analysis to standard clinical practice there must be a concurrent drive towards standardisation irrespective of the software package used. Skeletal muscle is a very physiologically active tissue and the quantity and quality of skeletal muscle can have a direct impact on outcomes in patients with cancer. In Chapter 9 the effect of the systemic inflammatory response on body composition and outcomes in patients with operable colorectal cancer (n=650) is examined. In this study on univariate survival analysis, age, ASA, TNM stage, mGPS, BMI, SFI, visceral obesity (VO), SMI and SMD were significantly associated with overall survival (all p&lt;0.05). Furthermore, a low SMI and SMD were significantly associated with an elevated mGPS (&lt;0.05). On multivariate analysis, SMI (HR 1.50, 95%CI 1.04-2.18, p=0.031), SMD (HR 1.42, 95%CI 0.98-2.05, p=0.061) and mGPS (HR 1.44, 95%CI 1.15-1.79, p=0.001) remained independently associated with overall survival. This study therefore delineates the relationship between the loss of quantity and quality of skeletal muscle mass, the systemic inflammatory response and survival in patients with operable colorectal cancer. The results of Chapter 11 add further weight to the prognostic relationship between markers of the systemic inflammatory response, physical function and body composition in patients with advanced cancer (n=289). In this study ECOG-PS, mGPS, timed up and go (TUG), 2 minute walk test (2MWT), hand grip strength (HGS), combined objective performance tests (COPT), SMI and SMD had prognostic value (all p&lt;0.05). However, none of these factors, with the exception of HGS (HR 1.63, 95%CI 1.03–2.59, p=0.04), displaced the prognostic value of ECOG-PS within the ECOG-PS/mGPS framework. These results validate the clinical utility of the ECOG-PS/mGPS framework in the assessment of patients with advanced cancer. Furthermore, in Chapter 12 the results of the longitudinal monitor of body composition in patients with operable colorectal cancer (n=470) have shown that the majority of patients did not change their SMI (81%) or SMD (72%) status on follow-up. In male patients those who maintained a low SMI were older (p&lt;0.001), received less adjuvant chemotherapy (p&lt;0.05), had a higher mGPS/NLR (both p&lt;0.05), had a BMI≥25, had pre-op VO and follow up VO (all p&lt;0.01). In female patients those who maintained a low SMI were older (p&lt;0.01), had more open surgery (p&lt;0.05), had a higher mGPS (p&lt;0.05), had a BMI≥25, had pre-op VO and follow up VO (all p&lt;0.01). On Cox-regression analysis patients who maintained a low SMI and SMD on follow up had worse overall survival (p&lt;0.05). However, when adjusted for age, sex, TNM stage and mGPS neither a maintained low SMI nor SMD was independently associated with survival. This suggests that a low skeletal muscle mass and quality are established early in the disease course, maintained following resection of the primary tumour and associated with VO and the presence of a systemic inflammatory response. The relationship between tumour metabolic activity and the systemic inflammatory response was examined in Chapter 13. This systematic review contained twelve studies including 2,588 patients and showed that the majority of studies showed a direct relationship between the tumour and bone marrow glucose uptake as measured by positron emission tomography CT (PET-CT) scanning and the host systemic inflammatory responses as measured by CRP (n=2), albumin (n=2), WCC (n=3), neutrophils (n=2) and platelets (n=2). The majority of the studies (n=8) also showed a direct relationship between tumour and bone marrow glucose uptake and poor outcomes. This suggests a direct relationship between the tumour and bone marrow glucose uptake and host systemic inflammation. This may suggest new approaches for more optimal therapeutic targeting and monitoring strategies in patients with cancer. Furthermore, Chapter 14 showed in patients undergoing curative radiotherapy for lung cancer (n=119) that on univariate survival analysis, lung cancer stage (p&lt;0.01), mGPS (p&lt;0.05), NLR (p&lt;0.01), SMD (p&lt;0.05) and Total Lesion Glycolysis (TLG, p&lt;0.001) were associated with overall survival. An elevated TLG was associated with sex (p&lt;0.05), TNM stage (p&lt;0.001), mGPS (p&lt;0.01) and maximized standardised uptake values (SUVmax, p&lt;0.001). On multivariate survival analysis only a TLG&gt;68.89 (HR:2.03, 95%CI 1.35-3.07, p&lt;0.001) remained independently associated with OS. This suggests that Tumour glucose uptake was associated with activation of the systemic inflammatory response but not lower skeletal muscle mass in patients with lung cancer. This suggests that the early targeting of the systemic inflammatory response could provide a fruitful treatment strategy aimed at maintaining skeletal muscle mass and function while also improving quality of life and outcomes in patients with cancer. In summary, the systemic inflammatory response has a direct relationship with changes in body composition and outcomes in patients with cancer. Interestingly this association would seem to be independent of tumour metabolic activity and potentially tumour stage. Cancer related changes in body composition and their associated effect on performance status seem to be established early in the disease process and maintained despite treatments targeting the tumour specifically, be they oncological or surgical. Given that an elevated systemic inflammatory response is not currently targeted, the present results would suggest that the die is cast in these patients. However, it may be that new treatment strategies targeting the inflammatory response as early as possible in the disease progression may arrest or reverse any skeletal muscle loss and improve outcomes in patients with cancer.