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Introduction: Besides tumor characteristics, colorectal cancer progression and survival is also determined by host factors, in particular a systemic inflammatory response (Glasgow Prognostic Score/GPS). The basis of this stage independent relationship with survival is unclear, however pre-op systemic inflammation may reflect comorbidity. Indeed, validated scores such as elevated Charlson comorbidity index (CCI), National Institute on Aging/National Cancer Institute (NIA/NCI) Index and Adult Comorbidity Evaluation-27 (ACE-27) are related to poor colorectal cancer survival. This study examines the relationships between pre-op comorbidity, systemic inflammation (GPS) and survival in colorectal cancer.Methods: Patients having elective curative resection were studied (n=302,1997-2005). A pre-op C-reactive protein>10mg/L and albumin<35g/dl each score 1 and the GPS is constructed (GPS 0, 1 or 2). Comorbidity data was abstracted from casenotes review. Patients were classified by 4 separate scores; the CCI, NIA/NCI index, ACE-27 and Lee Cardiac Risk Index (LCRI). Deprivation category, smoking status and body mass index (BMI) was collected.Results: Most were >65yrs (66%), Stage I/II disease (60%), a normal GPS (62%) and had a low comorbidty burden. Median follow-up was 74 months during which 135 died (85 from cancer). On multivariate analysis for cancer survival, age (HR 1.30,P=0.057), TNM stage (HR 2.73,P<0.001), LCRI (HR 1.38,P=0.014) and GPS (HR 1.85,P<0.001) were independently related. On multivariate analysis for overall survival, age (HR 1.50,P<0.001), TNM stage (HR 1.84,P<0.001), ACE-27 (HR 1.31,P=0.005) and the GPS (HR 1.61,P<0.001) were independently related. Results were similar in node negative disease (n=180).Old age was related to increasing comorbidity (ACE-27, CCI, LCRI (all P<0.005)) and elevated GPS (P<0.005). High BMI was related to higher comorbidity assessed with CCI, ACE-27 and NCI/NIA scores (all P<0.01). Smoking history and deprivation were related to increasing burden of comorbidity (all P<0.05). GPS had a weak association with comorbidity burden assessed with the ACE-27 (P=0.065), CCI (P=0.016), LCRI (P=0.095) and the NIA/NCI index (P=0.084).Discussion: Pre-op comorbidity measures, particularly Lee cardiac risk index are important indicators of cancer survival. Generalised comorbidity does not explain the relationship between the systemic inflammatory response and survival. The tumor and its response to therapy form the mainstay of current cancer reatment, however it is increasingly apparent novel “host-related” targets may be important. These include attenuation of the host inflammatory response and optimisation of host physiology.