Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients

Abstract

Objective To evaluate the efficacy and safety of the interleukin‐1 inhibitor rilonacept (interleukin‐1 Trap) for gout flare prevention during initiation of uric acid–lowering therapy (ULT). Methods In total, 241 adult patients with gout, ≥2 gout flares within the past year, and a serum urate level ≥7.5 mg/dl were initiated on allopurinol 300 mg daily and randomly allocated in a 1:1:1 ratio to receive 16 once‐weekly subcutaneous injections of placebo, rilonacept 80 mg, or rilonacept 160 mg, with a double (loading) dose on day 1. Allopurinol was titrated to achieve a serum urate level of <6.0 mg/dl. The study was powered for the primary efficacy end point, the number of gout flares per patient through week 16. Results More patients in the rilonacept groups (80.0% in the rilonacept 80 mg group, 86.4% in the rilonacept 160 mg group) completed the study than in the placebo group (72.5%; P < 0.05 for the rilonacept 160 mg group versus the placebo group). Over 16 weeks, the mean number of gout flares per patient was significantly reduced by rilonacept treatment (placebo: 1.06, rilonacept 80 mg: 0.29 [P < 0.001], rilonacept 160 mg: 0.21 [P < 0.001]). Significantly lower proportions of patients reported ≥1 gout flares with rilonacept 80 mg (18.8%) and rilonacept 160 mg (16.3%) relative to placebo (46.8%; P < 0.001 for both). Except for injection site reactions (1.3% in the placebo group versus 8.8% in the rilonacept 80 mg group [P = 0.0635, post hoc analysis] and 19.8% in the rilonacept 160 mg group [P = 0.0001, post hoc analysis]), the incidence of adverse events was generally balanced among the treatment groups. Conclusion Rilonacept markedly reduced the occurrence of gout flares associated with the initiation of ULT. The efficacy and safety profile suggests that rilonacept may have the potential to improve long‐term disease control for some patients by improving adherence to ULT by reducing flares during the first months after ULT initiation.

Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study

“…In animals, both higher (Hanada et al, 2004) and lower ghrelin levels than controls are reported. Several studies showed higher ghrelin levels (Shimizu et al, 2003;Garcia et al, 2005) or higher levels only in subgroups (61% of 18 breast and colorectal cancer patients) (Wolf et al, 2006) in patients with CACS as compared to non-cachetic cancer patients or healthy controls; however, normal (Huang et al, 2007) ghrelin levels were reported as well. The differences of fasting levels of ghrelin in cancer patients may be explained by differences in BMIs, 20.7 kg m À2 in LD and 20.6 kg m À2 in UD, and 18.5 kg m À2 in others (Shimizu et al, 2003).…”

“…Morning fasting levels of ghrelin in patients (Shimizu et al, 2003;Garcia et al, 2005;Wolf et al, 2006;Huang et al, 2007) or animals (Hanada et al, 2004;Liu et al, 2006) with CACS are still poorly understood. In animals, both higher (Hanada et al, 2004) and lower ghrelin levels than controls are reported.…”

“…The safety and tolerability data support further exploration of the therapeutic potential of natural ghrelin, namely escalation of dose and frequency and chronic administration. The patient population may be stratified for baseline ghrelin levels (Garcia et al, 2005;Wolf et al, 2006), and other factors need to be controlled for, namely genetic alterations of the ghrelin gene (Holst and Schwartz, 2006), cytokine levels (Dixit et al, 2004), stress level (Kristenssson et al, 2006), hypogonadism (Strasser et al, 2006), patients' eating preferences (Blom et al, 2006), baseline food intake (Gilg and Lutz, 2006), and gastric emptying (Binn et al, 2006). These strategies may counteract the series of many negative cachexia phase III trials (EPA, cannabinoids) or single not confirmed studies (ATP, thalidomide), treating uniformly all patients having loss of weight and appetite, despite promising pathophysiological concepts.…”

“…In cancer patients with cachexia (various cancers, n ¼ 21 (Garcia et al, 2005); breast and colorectal cancer, n ¼ 18 (Wolf et al, 2006); lung cancer, n ¼ 21 (Shimizu et al, 2003)), ghrelin morning fasting levels were 1.3-to 1.5-fold higher than in those without cachexia and healthy controls. In contrast, ghrelin levels were normal in subgroups of patients in one study (39%) (Wolf et al, 2006) and all patients in another study (gastric and colorectal cancer, n ¼ 58) (Huang et al, 2007). Lower ghrelin values in patients with colorectal cancer (n ¼ 29) than in healthy controls (n ¼ 50) were also reported (D'Onghia et al, 2007).…”

Adipokines and ghrelin in gastric cancer cachexia

“…It is produced primarily by the mammalian gastric enteroendocrine cells of the oxyntic mucosa, likely the X/A-like cells [6] . It has been reported that there was an increase in the levels of total ghrelin in cachectic lung [7] , breast and colon [8] cancer patients. Ghrelin infusion has recently been shown to increase appetite in subjects with cancer-induced cachexia [9] .…”