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The present study prospectively assessed the influence of medical, sociodemographic, psychological, and lifestyle variables on physical, social/family, emotional, functional well-being and colorectal cancer-specific concerns in a population-based sample of colorectal cancer survivors.Participants (n=1822) were assessed at 6 and 24 months post-diagnosis. Predictor variables assessed at 6 months included socio-demographic and medical variables, symptoms/side-effects, body mass index, physical activity, optimism, social support, and cancer threat appraisal. Quality of life (QOL) was assessed at 6 and 24 months post-diagnosis using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C).For each QOL subscale and for the overall FACT-C scale, 6 month scores were the strongest predictor of QOL scores at 24 months post-diagnosis (e.g.β=0.447,p< 0.001 for overall QOL). Socio-demographic, medical, and psychosocial variables, but not lifestyle variables, differentially predicted domain specific QOL. Only cancer threat appraisal was associated with all five QOL domains.Cancer threat appraisal presents as a potentially modifiable variable for interventions seeking to improve QOL. Symptom management and lifestyle strategies to ameliorate the effects of co-morbidities, disease stage and troublesome symptoms such as faecal incontinence on QOL should also be included.