Aetiology of systemic inflammation and its link with prognosis in gastro-oesophageal cancer
Deans, Derek Andrew Christopher
INTRODUCTION: As the incidence of gastro-oesophageal cancer continues to increase accurate staging remains challenging and the general outlook for these patients is poor. As well as improving prognostic accuracy, investigation of systemic inflammation and cachexia in these patients may enable the identification of much needed novel therapeutic targets.AIMS: The aims of this thesis were to describe the genesis, mediators and clinical sequelae of systemic inflammation in patients with gastro -oesophageal cancer. The usefulness of systemic inflammation as a prognostic indicator and the role of cachexia as a factor in the adverse prognosis associated with systemic inflammation were expanded in detail. The key hypothesis being that tumour cells produce mediators (eg cytokines), which can either directly or indirectly (via systemic inflammation) induce a catabolic state in the peripheral tissues of the host. Such wasting may be one of the mechanisms linking systemic inflammation with adverse prognosis in patients with cancer.MATERIALS & METHODS: A consecutive series of 220 patients with gastric or oesophageal cancer were studied. Data were collected prospectively and a nutritional assessment and performance status were determined for each patient and survival duration was recorded. Samples of blood, urine and tumour tissue were collected for determination of cytokine and acute phase protein concentrations. The expression of other potential tumour -derived mediators, parathyroid hormone -related peptide (PTHrP) and proteolysis- inducing factor (PIF), were also studied.RESULTS: Systemic inflammation (CRP >10 mg /I) was present in 43% of patients with gastrooesophageal cancer. Serum acute phase protein concentrations (especially CRP), but not serum cytokine concentrations, were robust measures of systemic inflammatory activity. However, concentrations of pro -inflammatory cytokines within tumour tissue were significantly elevated and were linked with markers of systemic inflammation. IL-18 in particular was over - expressed in tumour tissue and may be a key determinant of systemic inflammation in patients with gastro -oesophageal malignancy. A chronic inflammatory cell infiltrate into the tumour tissue was present in 75% of tumours and was also linked with markers of systemic inflammation. Tumour cells or host immune cells or a combination of the two may be the main source of these mediators. The presence of systemic inflammation was also influenced by host cytokine genotype. Other potential tumour -derived mediators, such as PIF and PTHrP, may also play a (minor) role in the generation of systemic inflammation. These factors may also have additional effects on the host, such as potentiating weight loss. CRP concentrations were identified as the best marker of prognosis and the magnitude of serum CRP concentrations were negatively linked with survival duration.83% of patients had lost weight at the time of diagnosis and within 3 months this had increased to 92 %. Increasing weight loss was positively associated with serum markers of systemic inflammation. Weight loss among patients with gastro -oesophageal cancer was not accounted for entirely by reduced food intake or mechanical obstruction secondary to the tumour. Alternatively, the presence of systemic inflammation contributed to nutritional decline (estimate of effect 34 %). Weight loss was associated with adverse outcome and cachexia may be an aetiological factor involved in the link between systemic inflammation and adverse prognosis.CONCLUSIONS: Systemic inflammation, weight loss, performance status, and stage of disease were the main determinants of outcome in patients with gastro-oesophageal cancer. These factors were used to devise a novel model to improve prognostic accuracy to aid clinical decision-making for these patients. These studies identify systemic inflammation as both an important prognostic indicator and a potential therapeutic target for patients with gastro-oesophageal malignancy.