Interaction of gonadal status with systemic inflammation and opioid use in determining nutritional status and prognosis in advanced pancreatic cancer.

PURPOSE: Hypogonadism has been linked with systemic inflammation and opioid use in males with advanced cancer. We aimed to investigate the interaction of gonadal status with systemic inflammation and opioids in determining nutritional status and prognosis in advanced pancreatic cancer. METHODS: One hundred and seventy-five patients (92 males, 83 postmenopausal females) with unresectable pancreatic cancer were studied. Serum sex steroids (total testosterone [TT], calculated free testosterone [cFT], oestradiol, sex hormone binding globulin), gonadotropins (follicle-stimulating hormone and luteinising hormone) and pro-inflammatory mediators (C-reactive protein [CRP], interleukin-6 [IL-6], soluble tumour necrosis factor receptor 75 [sTNFR75]) were measured, and nutritional assessment and opioid use recorded. RESULTS: Seventy-three percent of males were hypogonadal (by cFT definition). cFT correlated positively with BMI (r (2) =0.349; p< 0.001) and grip strength (r (2) = 0.229; p = 0.034) and inversely with weight loss (r (2) = -0.287; p = 0.007), CRP (r (2) = -0.426; p < 0.001) and IL-6 (r (2) = -0.303; p = 0.004). CRP (p= 0.007), opioid dosage (p = 0.009) and BMI (p = 0.005) were independent determinants of cFT on ANOVA. Hypogonadal males demonstrated worsened survival compared with eugonadal patients (TT: OR of death = 2.87; p < 0.001; cFT: OR = 2.26; p = 0.011). Furthermore, male opioid use was associated with decreased TT (p < 0.001) and cFT (p < 0.001) and worsened survival (OR = 1.96; p = 0.012). In contrast, 18% of postmenopausal females exhibited premenopausal ("hyperoestrogenic") oestradiol levels. Oestradiol correlated positively with sTNFR75 (r (2) = 0.299; p = 0.008). CRP (p < 0.001) was an independent determinant of oestradiol. Hyperoestrogenic females demonstrated worsened survival compared with eugonadal patients (OR = 2.43; p = 0.013). CONCLUSIONS: In males with pancreatic cancer, systemic inflammation and opioid use are associated with hypogonadism. Male hypogonadism and female hyperoestrogenism are associated with shortened survival in advanced pancreatic cancer.

Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: relationship to acute phase response and survival.

The acute phase protein response (APPR) and peripheral blood mononuclear cell-derived inflammatory cytokine production was assessed in patients with advanced pancreatic cancer and age-matched healthy volunteers. We examined the relationship between the APPR, cytokine production and survival in these patients. Forty-two patients with pancreatic cancer cachexia and twelve age-matched healthy controls were recruited. The nutritional status, Karnofsky performance score, C reactive protein (CRP), serum interleukin-6, and in vitro monocyte interleukin-1 and interleukin-6 production were measured. The dates of death of the pancreatic cancer patients were subsequently obtained and appropriate patient variables at baseline were entered into a Cox's proportional hazards model. The cancer patients had significantly lower: body mass index, Karnofsky performance score, serum albumin and elevated CRP and stimulated interleukin-6 production. Both univariate and multivariate analysis demonstrated a strong association between tumour stage, CRP, stimulated interleukin-6 production and survival. Monocytes in cachectic pancreatic cancer patients are primed to produce high levels of interleukin-6 when stimulated. Overproduction of interleukin-6 has a negative impact on survival. Decreased survival is associated with an elevated APPR. While the elevated APPR is probably related to locally produced interleukin-6 in the liver, it seems possible that locally and systemically produced interleukin-6 influences survival.

Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia.

PURPOSE: Eicosapentaenoic acid (EPA) has been proposed to have specific anticachectic effects. This trial compared EPA diethyl ester with placebo in cachectic cancer patients for effects on weight and lean body mass. PATIENTS AND METHODS: Five hundred eighteen weight-losing patients with advanced gastrointestinal or lung cancer were studied in a multicenter, double-blind, placebo controlled trial. Patients were randomly assigned to receive a novel preparation of pure EPA at a dose of 2 g or 4 g daily or placebo (2g EPA, n = 175; 4 g EPA, n = 172; placebo, n = 171). Patients were assessed at 4 weeks and 8 weeks. RESULTS: The groups were well balanced at baseline. Mean weight loss at baseline was 18% (n = 518). Over the 8-week treatment period, both intention-to-treat analysis and per protocol analysis revealed no statistically significant improvements in survival, weight, or other nutritional variables. There was, however, a trend in favor of EPA with analysis of the primary end point, weight, at 8 weeks showing a borderline, nonsignificant treatment effect (P = .066). Relative to placebo, mean weight increased by 1.2 kg with 2 g EPA (95% CI, 0 kg to 2.3 kg) and by 0.3 kg with 4 g EPA (-0.9 kg to 1.5 kg). CONCLUSION: The results indicate no statistically significant benefit from single agent EPA in the treatment of cancer cachexia. Future studies should concentrate on other agents or combination regimens.

Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia.

Muscle wasting in experimental cancer cachexia has been associated with increased ubiquitin proteasome proteolytic system activity and increased uncoupling protein (UCP) expression. Increased ubiquitin proteasome pathway activity has also been found in gastric, but not lung, cancer patients. It therefore remains unclear in which patients modulation of this proteolytic system could be a therapeutic target. We investigated markers of systemic inflammation, hypermetabolism and expression of ubiquitin and uncoupling proteins 2 and 3 in muscle of pancreatic cancer patients. Rectus abdominis muscle was sampled from 15 weight-losing pancreatic cancer patients and 11 controls. UCP2 and 3, and ubiquitin mRNA expression were measured by Northern blots and UCP3 protein by Western blotting. Resting energy expenditure and plasma IL-6, sTNF-R and C-reactive protein (CRP) were also measured. Cancer patients had lost 18% of pre-illness stable weight, but were not significantly hypermetabolic compared with controls. IL-6, sTNF-R and CRP levels and ubiquitin 2.4 kb, but not 1.2 kb, mRNA expression were increased in cancer patients. UCP-2 and 3 mRNA and UCP-3 protein were similar in both groups. Weight loss correlated with systemic inflammation and ubiquitin 1.2 and 2.4 kb mRNA expression. Weight loss in pancreatic cancer is associated with systemic inflammation and increased mRNA expression for ubiquitin but not uncoupling proteins in skeletal muscle. The pro-inflammatory network and ubiquitin proteasome pathway may be targets for intervention in pancreatic cancer cachexia.

Cancer cachexia.

Cancer cachexia is a complex, multifactorial syndrome that results from a reduction in food intake, a variety of metabolic abnormalities (including hypermetabolism) or more often a combination of the two. Multiple mediator pathways including pro-inflammatory cytokines, neuroendocrine hormones and tumour-specific factors are involved. Therapy requires a multi-model approach that addresses both reduced food intake and metabolic change. Combination treatments such as nutritional support plus metabolic/inflammation modulation promise improved functional capacity and quality of life.