Giorgia Antoni

Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib ± megestrol acetate for patients with cancer-related anorexia/cachexia syndrome

BACKGROUND & AIMS A phase III, randomized non-inferiority study was carried out to compare a two-drug combination (including nutraceuticals, i.e. antioxidants) with carnitine + celecoxib ± megestrol acetate for the treatment of cancer-related anorexia/cachexia syndrome (CACS): the primary endpoints were increase of lean body mass (LBM) and improvement of total daily physical activity. Secondary endpoint was: increase of physical performance tested by grip strength and 6-min walk test. METHODS Sixty eligible patients were randomly assigned to: arm 1, L-carnitine 4 g/day + Celecoxib 300 mg/day or arm 2, L-carnitine 4 g/day + celecoxib 300 mg/day + megestrol acetate 320 mg/day, all orally. All patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, carbocysteine 2.7 g/day, Vitamin E, A, C. Treatment duration was 4 months. Planned sample size was 60 patients. RESULTS The results did not show a significant difference between tre atment arms in both primary and secondary endpoints. Analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) increased significantly in both arms as well as physical performance assessed by 6MWT. Toxicity was quite negligible and comparable between arms. CONCLUSIONS The results of the present study showed a non-inferiority of arm 1 (two-drug combination) vs arm 2 (two-drug combination + megestrol acetate). Therefore, this simple, feasible, effective, safe, low cost with favorable cost-benefit profile, two-drug approach could be suggested in the clinical practice to implement CACS treatment.

Persistence, Up to 18 Months of Follow-Up, of Epirubicin-Induced Myocardial Dysfunction Detected Early by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers

A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated cancer patients with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. Thirty-one patients (male/female ratio, 8/23; mean age +/- standard deviation, 59 +/- 14 years) with tumors at different sites and scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled. We prospectively evaluated the acute (1 week after) and late (3, 6, 12, and 18 months of follow-up) effects of epirubicin administration. A significant impairment in systolic left ventricular (LV) function was observed at a cumulative epirubicin dose of 200 mg/m(2). This was shown by a reduction in the strain rate (SR) peak in comparison with baseline and persisted throughout the treatment and follow-up, up to 18 months; strain (Sigma) remained unchanged. The Sm wave showed a progressive reduction that became significant only at the 18-month follow-up. On TDI the E(m)/A(m) ratio declined at the 200-mg/m(2) cumulative epirubicin dose versus baseline and persisted throughout the treatment and up to the 18-month follow-up. On conventional echocardiography the E/A ratio declined significantly only at the 300-mg/m(2) cumulative epirubicin dose. Interleukin (IL)-6, soluble IL-6 receptor, and reactive oxygen species (ROS) increased significantly at the 200-mg/m(2) dose, and IL-6 was persistently high at the 300- and 400-mg/m(2) doses, returning to within baseline values during follow-up. ROS, after the peak reached at the 200-mg/m(2) dose, returned to within baseline values. A significant inverse correlation between DeltaSR and the increase in both IL-6 and ROS was observed. A multiple regression analysis showed that both the IL-6 and ROS variables were independent and strongly predictive of DeltaSR. The clinical meaningfulness of our findings warrants further investigations on a larger number of patients for a longer period of follow-up.

Energy expenditure in caving

The aim of this study was to determine the energy expenditure of a group of cavers of both genders and different ages and experience during a 10 hour subterranean exploration, using portable metabolimeters. The impact of caving activity on body composition and hydration were also assessed through bioelectrical impedance, and nutritional habits of cavers surveyed. During cave activity, measured total energy expenditure (TEE) was in the range 225–287 kcal/h for women-men (MET = 4.1), respectively; subjects had an energy intake from food in the range 1000–1200 kcal, thus inadequate to restore lost calories. Bayesian statistical analysis estimated the effect of predictive variables on TEE, revealing that experienced subjects had a 5% lower TEE than the less skilled ones and that women required a comparatively larger energy expenditure than men to perform the same task. BIVA (bioelectrical impedance vector analysis) showed that subjects were within the range of normal hydration before and after cave activity, but bioelectrical changes indicated a reduction of extracellular water in men, which might result in hypo-osmolal dehydration in the case of prolonged underground exercise. All these facts should be considered when planning cave explorations, preparing training programs for subjects practising caving, and optimizing a diet for cavers. Further, information gathered through this study could be of value to reduce accidents in caves related to increase in fatigue.

Long-term protective effects of the angiotensin-receptor blocker telmisartan on epirubucin-induced inflammation, oxidative stress, and myocardial dysfunction.

9030 Background: Chronic inflammation, oxidative stress and renin-angiotensin system (RAS) play a significant role in chemotherapy-induced cardiotoxicity (CTX): telmisartan (Tel), an antagonist of angiotensin II type-1 receptor, has shown to be able to reduce anthracycline (ANT)-induced CTX. METHODS We carried out a phase II placebo-controlled randomized trial, to assess the possible role of Tel in the prevention of the cardiac sub-clinical damage induced by epirubicin (EPI). Forty-nine patients (mean age ± SD 53.0±8 years), cardiovascular disease-free with cancer at different sites and eligible for EPI- based treatment, were randomized to one of two arms: Tel n=25; Placebo (PLA) n=24. A conventional echocardiography equipped with Tissue Doppler Imaging, Strain and Strain Rate was performed as well as serum levels of proinflammatory cytokines IL-6 and TNF-a and oxidative stress parameters reactive oxygen species (ROS) and glutathione peroxidase (GPx). All assessments were carried out at baseline, every 100 mg/m2 of EPI dose and at 3, 6 and 12 month-follow up (FU). RESULTS A reduction of the SR peak comparable between the two arms was observed at the dose of 200 mg/m2 EPI, whereas, at 300 and 400 EPI doses, the SR turned out to increase reaching the normal range only in the Tel arm. The differences between SR changes in the PLA and Tel arm were significant from t3 up to 12 month-FU. Serum levels of IL-6 increased significantly in the PLA arm at t2 in comparison to baseline but remained unchanged in the Tel arm. The same trend was shown by ROS levels which significantly increased at t2 versus baseline in the PLA arm, whilst remained unchanged in the Tel arm. The mean change of ROS and IL-6 at t2 was significantly different between the 2 arms. In the present study, we confirm at 3 month-FU the trend toward a decrease of ROS and IL-6 from t2 in the PLA arm. CONCLUSIONS Our results suggest that Tel is able to prevent not only the acute (early) but even the late (up to 12 month-FU) EPI-induced myocardial dysfunction. These effects are likely to be due to different mechanisms: RAS blockade and prevention of chronic inflammation/oxidative stress.

1261 POSTER Long-term Protective Effects of the Angiotensin Receptor Blocker Telmisartan on Epirubicin-induced Inflammation, Oxidative Stress and Myocardial Dysfunction

Chronic inflammation, oxidative stress and the renin-angiotensin system (RAS) play a significant role in chemotherapy-induced cardiotoxicity (CTX). Telmisartan (TEL), an antagonist of the angiotensin II type-1 receptor, was found to reduce anthracycline (ANT)-induced CTX. We carried out a phase II placebo (PLA)-controlled randomized trial to assess the possible role of TEL in the prevention of cardiac subclinical damage induced by epirubicin (EPI). Forty-nine patients (mean age ± SD, 53.0±8 years), cardiovascular disease-free with cancer at different sites and eligible for EPI-based treatment, were randomized to one of two arms: TEL n=25; PLA n=24. A conventional echocardiography equipped with Tissue Doppler imaging, strain and strain rate (SR) was performed, and serum levels of proinflammatory cytokines, IL-6 and TNF-α, and oxidative stress parameters, reactive oxygen species (ROS) and glutathione peroxidase were determined. All assessments were carried out at baseline, after every 100 mg/m(2) of EPI dose and at the 12-month follow-up (FU). A significant reduction in the SR peak both in the TEL and PLA arms was observed at t(2) (cumulative dose of 200 mg/m(2) of EPI) in comparison to t(0). Conversely, at t(3) (300 mg/m(2) EPI), t(4) (400 mg/m(2) EPI) and the 12-month FU, the SR increased reaching the normal range only in the TEL arm, while in the PLA arm the SR remained significantly lower as compared to t(0) (baseline). The differences between SR changes in the PLA and TEL arms were significant from 300 mg/m(2) EPI (t(3)) up to the 12-month FU. Serum levels of IL-6 increased significantly in the PLA arm at 200 mg/m(2) EPI (t(2)) in comparison to baseline, but remained unchanged in the TEL arm. The same trend was demonstrated for ROS levels which significantly increased at t(2) vs. baseline in the PLA arm, while remained unchanged in the TEL arm. The mean change in ROS and IL-6 at t(2) was significantly different between the two arms. In the present study, we confirmed at the 3-month FU a trend toward a decrease in ROS and IL-6 from t(2) in the PLA arm. Our results suggest that TEL is able to reverse acute (early) EPI-induced myocardial dysfunction and to maintain later a normal systolic function up to the 12-month FU. These effects are likely to be due to different mechanisms, RAS blockade and prevention of chronic inflammation/oxidative stress.

Correction: Energy expenditure in caving

[This corrects the article DOI: 10.1371/journal.pone.0170853.].

Abstract 5223: Correlation between both serum osteopontin/osteonectin and bone remodelling parameters, inflammatory/metabolic variables and survival in metastatic cancer patients with tumors at different sites

Background: Osteopontin (OPN) is a secreted, integrin-binding phosphoprotein that has been correlated with tumor grade and stage and disease progression in several tumor types. Moreover, high OPN levels have been clinically correlated with metastatic bone disease and bone resorption in cancer patients. The “secreted protein, acidic and rich in cystein” (SPARC) is closely related to progression, invasion, angiogenesis and metastatic process of several malignant tumors. Aim of the study: The aim of the study was to verify in a population of advanced cancer patients with tumors at different sites whether there is a correlation between circulating levels of OPN and SPARC and clinical parameters (such as bone metastases, pain and quality of life), circulating bone remodeling (skeletal) parameters (alkaline phosphatase, C- and N-terminal fragments of type I collagen, osteocalcin, Vitamin D), inflammatory (IL-8 and TNF-alpha) and metabolic parameters (BMI, serum cholesterol and triglycerides). The correlation between OPN and SPARC and survival was also assessed. Patients and Methods: From April 2010 to August 2010, we enrolled 33 metastatic cancer patients with tumors at different sites (M/F: 16/17, mean age 66 years): 17 patients with bone metastases, 16 with metastases not involving bone. OPN and SPARC were measured using an antigen-capture enzyme-linked immunosorbent assay technique. BMI, pain by analogical visual scale and quality of life by EORTC QLQ C30 were assessed. Comparison between groups (controls vs cancer patients and cancer patients with vs without bone metastases) was performed by two-sided Student9s t test. Correlation between OPN/SPARC and the other variables was performed by Spearman9s correlation analysis. Results: OPN and SPARC in cancer patients were significantly higher compared to controls but did not differ between patients with or without bone metastases. OPN showed a positive significant correlation with C and N terminal fragments of type I collagen (r=0.390 and r=0.410, p=0.024 for both), IL-8 (r=0.390, p=0.034) and a negative significant correlation with quality of life (r=−0.400, p=0.025) and BMI (r=−0.300, p=0.046). SPARC showed a positive significant correlation with BMI (r=0,360, p=0.049). Moreover, patients with ≤3 month survival showed significantly higher levels of OPN in comparison to patients with > 3 month survival (613.7+/-229.2 ng/ml versus 195.8 +/- 165 ng/ml, p Conclusions: The results of the present study show that high OPN levels are associated with poor survival in advanced cancer patients. Further studies are warranted to assess the role of OPN and SPARC to both monitor the effects of antineoplastic regimens and to assess them as potential targets of new treatment strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5223. doi:10.1158/1538-7445.AM2011-5223

Abstract 3724: Efficacy and safety of the COX-2 inhibitor celecoxib on patients with cancer cachexia: a phase II non randomized study

Chronic inflammation is one of the main features of cancer cachexia. Experimental and clinical studies showed that cyclooxygenase (COX)-2 inhibitors, such as celecoxib, may be beneficial in counteracting major symptoms of this devastating syndrome. We carried out a prospective non randomised phase II clinical trial to test the safety and effectiveness of an intervention with the COX-2 inhibitor celecoxib (300 mg/day for 4 months) on key variables of cachexia (lean body mass, resting energy expenditure, serum levels of proinflammatory cytokines, and fatigue) in patients with advanced cancer at different sites. Patient eligibility criteria were: age range of 18-80 years, histologically confirmed tumor of any site at an advanced stage, loss of ≥5% of body weight in the previous 3 months and a life expectancy of ≥4 months. Patients could be receiving concomitant antineoplastic chemotherapy or hormone therapy with palliative intent or supportive care. Exclusion criteria were: women of child-bearing age, positive history of heart disease, history of previous myocardial infarction, unstable angina, coronary revascularization, uncontrolled arrhythmia, congestive heart failure and cerebrovascular accident, previous gastrointestinal inflammatory disease and history of gastrointestinal ulceration, mechanical obstruction to feeding, and medical treatments inducing significant changes of patient metabolism or body weight. A sample of 24 patients was enrolled from January to December 2008 and all were deemed assessable. The men/women ratio was well balanced (13/11). The mean age was 60.6 years. The most frequent tumor sites were head and neck, lung, and colorectal. Patients were >90% stage IV and the Glasgow Prognostic Score (GPS), an inflammation-based score predictive of patient survival, was high (two) in 50% of them. Among primary efficacy endpoints, LBM assessed both by BIA (mean increase, +0.6±2.4 kg) and DEXA (mean increase, +0.6±2.7 kg) increased significantly (p Among secondary efficacy endpoints, an improvement of grip strength, quality of life, performance status, and Glasgow prognostic score was shown. There were no grade 3/4 toxicities. Patient compliance was very good; no patient had to reduce the celecoxib dosage nor interrupt treatment. Our results show that the COX-2 selective inhibitor celecoxib is an effective single agent for the treatment of cancer cachexia. Therefore, phase III clinical trials are warranted to test the efficacy and safety of celecoxib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3724.