It has not been well established whether the oxidative stress found in cancer patients results from an increased production of oxidants in the body or from a failure of physiological antioxidant ...systems. To further investigate this question, we have assessed the blood levels of reactive oxygen species as a marker of free radicals producing oxidative stress and the most relevant of the physiological body enzymes counteracting reactive oxygen species, namely glutathione peroxidase and superoxide dismutase. We also investigated serum levels of proinflammatory cytokines and IL-2. All of these parameters were studied in relation to the most important clinical index of disease progression--namely, the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS). We also tested the reducing ability of different antioxidant agents on reactive oxygen species levels by measuring the increase in glutathione peroxidase activity and the reduction of serum levels of IL-6 and TNF-alpha.
We carried out an open nonrandomized study on 28 advanced stage cancer patients (stage III, 10.7% and stage IV, 89.3%) with tumors at different sites. The patients were divided into 5 groups, and a different antioxidant treatment was administered to each group. The antioxidants were alpha lipoic acid 200 mg/day orally; N-acetylcysteine 1800 mg/day i.v. or carboxycysteine-lysine salt 2.7 g/day orally; amifostine 375 mg/day i.v.; reduced glutathione 600 mg/day i.v.; and a combination of vitamin A 30,000 IU/day orally, vitamin E 70 mg/day orally, and vitamin C 500 mg/day orally. The antioxidant treatment was administered for 10 consecutive days.
We found that all but one of the antioxidants tested were effective in reducing reactive oxygen species levels, and two of them (cysteine-containing compounds and amifostine) had the additional effect of increasing glutathione peroxidase activity. Comprehensively, the antioxidant treatment was found to have an effect on both reactive oxygen species levels and glutathione peroxidase activity. The antioxidant treatment also reduced the serum levels of IL-6 and TNF-alpha. Patients in both ECOG PS 0-1 and ECOG PS 2-3 responded to antioxidant treatment.
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Background: Cancer progression is characterized by specific energy metabolism alterations and by symptoms including fatigue, anorexia, nausea, depression, which results in cachexia ...syndrome and compromised quality of life (QL). This condition is often associated to anemia (cancer-related anemia, CRA), which negatively impacts patient QL and disease outcome. Methods: Adult advanced cancer patients with cachexia (i.e., weight loss > 5% in the previous 6 months) and CRA were randomly assigned (1:1 by computer generated list) to receive 3 months of a combined approach consisting of celecoxib (200 mg/day), L-carnitine (2 g/day), curcumin (Meriva) (4 g/day) and lactoferrin (200 mg/day) or placebo. The rationale for selecting these agents was: L-carnitine for modulating cell energy metabolism; celecoxib for counteracting inflammation, which is a key feature of cachexia; curcumin for its antiinflammatory and antioxidant action, without disregarding its action on the NF-kB and JAK-STAT pathway and the related synthesis of proinflammatory cytokines; lactoferrin for its ability to regulate iron metabolism in anemic cancer patients. Primary endpoints were improvement of lean body mass (LBM), appetite, fatigue and anemia. Additionally, we assessed the impact of treatment on the main metabolic/inflammatory and iron metabolism parameters: C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, leptin, reactive oxygen species (ROS), glutathione peroxidase, serum iron, ferritin, hepcidin and erythropoietin (EPO). Results: From January 2013 to March 2014, 66 patients have been enrolled. The combination arm was more effective than placebo arm in improving body weight, LBM, appetite, fatigue, and anemia. Among secondary parameters IL-6, TNF-α, CRP, ROS, ferritin, hepcidin and EPO decreased, while leptin increased significantly in the combination arm. No significant changes were observed in the placebo arm. Conclusions: To date a standard effective treatment of cancer cachexia is lacking. Our combined multitargeted approach was able to improve the nutritional and immunometabolic alterations of cachexia, ameliorate patient QL and correct CRA.
Anemia occurs in more than 30% of patients with epithelial ovarian cancer before any surgery. High levels of proinflammatory cytokines and increased oxidative stress may contribute to the development ...of cancer-related anemia. We assessed a population of previously untreated patients with advanced epithelial ovarian cancer to evaluate whether there was a correlation between hemoglobin (Hb) and parameters of inflammation and oxidative stress, stage of disease, and performance status (PS). In 91 patients with epithelial ovarian cancer and 95 healthy women matched for age, weight, and height, levels of Hb, C-reactive protein (CRP), fibrinogen (Fbg), proinflammatory cytokines, leptin, reactive oxygen species (ROS), and antioxidant enzymes were assessed at diagnosis before treatment. The correlations between Hb, parameters of inflammation and oxidative stress, stage, and PS were evaluated. Hb levels were lower in patients with advanced epithelial ovarian cancer than in control subjects and inversely related to stage and PS. Hb negatively correlated with CRP, Fbg, interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNFα), and ROS, and positively correlated with leptin and glutathione peroxidase (GPx). Multivariate regression analysis showed that stage and IL-6 were independent factors determining Hb values. This evidence suggests that anemia in epithelial ovarian cancer is common and its presence is related to stage of disease and markers of inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The primary aim of the present study was to examine the relationship of changes in hemoglobin levels following recombinant human erythropoietin (rHuEPO) treatment to changes in cognitive functioning ...studied by Mini Mental State Examination (MMSE) in elderly cancer patients undergoing chemotherapy treatment. The secondary aim was that to assess the relationship of changes in hemoglobin levels following rHuEPO treatment to changes in functions studied by Comprehensive Geriatic Assessment (CGA), such as Activity of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Geriatric Depression Scale (GDS) and the Mini Nutritional Assessment (MNA). To this end, hemoglobin levels and cognitive functioning were evaluated in a sample of cancer patients prior to the start of chemotherapy treatment and again after 4, 8 and 12 weeks of treatment with chemotherapy plus rHuEPO. Ten elderly patients (mean age 71.4 years) were enrolled. At baseline, enrolled patients had a mean Hb value of 10.3
g/dl. After 4 weeks of rHuEPO treatment, Hb values increased significantly (
p
<
0.0001), with a mean increase of 1.2
g/dl (range: 0.2–2.1). Remarkably, 8 out of 10 (80%) showed an increase of Hb levels ≥1
g/dl in comparison to baseline and therefore were considered responders. At baseline, four patients (40%) showed a moderate cognitive impairment, whilst six patients (60%) showed a normal cognitive function. After 4 weeks of rHuEPO treatment nine patients (90%) showed a significant improvement of cognitive functions in comparison to baseline (
p
<
0.005): eight of them were responders also to rHuEPO in terms of correction of anemia. The Spearman's rank correlation test showed a statistical significant correlation between Hb increase and increase in cognitive functioning assessed by MMSE after 4 weeks (
p
=
0.049), 8 weeks (
p
=
0.044) and 12 weeks (
p
=
0.031) of rHuEPO treatment. Therefore, the findings of this study provide support for the hypothesis that significant increases in hemoglobin over the course of chemotherapy supplemented with rHuEPO administration would be accompanied by significant improvement in cognitive performance over the same interval.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In the present study we tested the ability of different antioxidant agents, used alone or in combination, to reduce the reactive oxygen species (ROS) levels and to increase the glutathione peroxidase ...(GPx) activity. Moreover, we tested the ability of such antioxidant agents to reduce the serum levels of proinflammatory cytokines IL-6 and TNF f . Fifty-six advanced stage cancer patients with tumors at different sites were included in the study: they were mainly stage III (12.5%) and stage IV (82.1%). The study was divided into two phases. In the 1 st phase 28 patients were divided into five groups and a single different antioxidant agent was administered to each group. The selected antioxidant agents were: alpha lipoic acid or carboxycysteine-lysine salt, amifostine, reduced glutathione, vitamin A plus vitamin E plus Vitamin C. In the 2 nd phase of the study 28 patients were divided into five groups and a combination of two different antioxidant agents was administered to each group. The antioxidant treatment was administered for 10 consecutive days. The patients were studied at baseline and after antioxidant treatment. Our results show that all single antioxidants tested were effective in reducing the ROS levels and three of them in increasing GPx activity, too. Among the combinations of antioxidant agents, three were effective in reducing ROS, while three were effective in increasing GPx activity (arm 4 was effective in both instances). Comprehensively, the "antioxidant treatment" was found to be effective both on ROS levels and GPx activity. Moreover, the antioxidant treatment was able to reduce serum levels of IL-6 and TNF f . Furthermore, a correlation was shown between the Eastern Cooperative Oncology Group Performance Status of patients and blood levels of ROS, GPx activity, serum levels of proinflammatory cytokines.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of ...proinflammatory cytokines, such as interleukin 6, tumor necrosis factor alpha, and interferon gamma, have been proposed as mediators of cancer cachexia; these data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. We therefore studied the relationship between serum leptin and serum cytokines interleukin 6 and tumor necrosis factor alpha levels in advanced-stage cancer patients. Twenty-nine advanced stage cancer patients (all but one stage IV) with tumors at various sites were included in the study. A direct correlation between body mass index and serum leptin levels was found both in cancer patients and in healthy individuals. The serum levels of interleukin 6 were significantly higher in cancer patients than in healthy individuals. In cancer patients an inverse correlation was found between serum levels of leptin and proinflammatory cytokines. There was an inverse correlation between the Eastern Cooperative Oncology Group performance status scale and serum levels of leptin. Regarding survival, patients with very high serum levels of proinflammatory cytokines and very low levels of leptin had very short survival. Although obtained in a cancer patient population not overtly cachectic, our results provide further evidence that a simple dysregulation of leptin production and/or release cannot be involved in cancer-associated pathophysiological changes leading to cachexia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In the present open non-randomized phase II study we looked for effectiveness, safety, tolerability and costs of locally applied GM-CSF in preventing or treating mucositis in patients receiving ...chemotherapy or chemoradiotherapy for head and neck cancer. In addition to clinical mucositis scoring system, the effects of treatment with GM-CSF were evaluated by its impact on patient quality of life and by laboratory immunological assays such as serum proinflammatory cytokines, IL-2 and leptin. The trial was designed to assess the effectiveness of local GM-CSF treatment in two different settings: i) prophylaxis of mucositis; ii) treatment of mucositis. Prophylaxis was chosen for chemoradiotherapy treatments of high mucosatoxic potential, while curative treatment was reserved for chemotherapy or chemoradiotherapy treatments of lesser potential of inducing mucositis. From January 1998 to December 2001, 68 patients entered the study. The great majority of patients of both groups had head and neck cancer, were stage IV, PS ECOG 0-1, were habitual smokers and were treated with chemotherapy and concomitant (or sequential) chemoradiotherapy. Forty-six patients were included in the 'prophylactic' setting and 22 patients in the 'curative' setting. The main findings of our study are: only 50% of patients included in the 'prophylactic' setting developed mucositis; the duration of oral mucositis from appearance until complete remission was significantly shorter in the 'prophylactic' than in the 'curative' setting; the mean grade of oral mucositis at baseline, on day 3 of therapy and on day 6 of therapy was significantly lower in the 'prophylactic' than in the 'curative' setting; 24 (55.82%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis at baseline compared to 25 (80.60%) patients in the 'curative' setting (p=0.048). Thirteen (30.23%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis on day 3 of therapy compared to 19 (61.29%) patients in the 'curative' setting (p=0.015); 'prophylactic' setting was able to shorten grade 3/4 oral mucositis to grade 0/1 more effectively than the 'curative' one on day 6 of therapy (p=0.05). The present clinical trial is to date by far the largest study assessing the effectiveness of topical GM-CSF and it is the first study comparing the efficacy of topical GM-CSF in the 'prophylactic' setting, i.e., with the aim to prevent the chemoradiotherapy-induced oral mucositis, with that in the 'curative' treatment, i.e., the therapy for established oral mucositis. The topical application of GM-CSF was demonstrated to be effective for oral mucositis induced by chemotherapy and chemoradiotherapy regimens. Moreover, the 'prophylactic' setting was demonstrated to be more effective than the 'curative' one.
The primary aim of this study was to find whether any association exists between serum levels of proinflammatory cytokines, mainly IL-6, and the most important comprehensive geriatric assessment ...(CGA) variables such as functional status, cognitive functions and nutrition in a population of elderly cancer patients. The secondary aims were to find whether any difference existed between: i) age groups, ii) performance status scores, iii) patients who had lost weight versus those who had not. Eighty-four elderly patients with advanced cancer were included in the study (stage III 15.4%, and stage IV 72.6%). Serum levels of IL-6 and CRP were significantly higher in elderly than in the other adult cancer patients. Among the CGA variables investigated, the most affected were functional status assessed by IADL, cognitive functions by MMSE and nutrition. The ECOG PS was shown to be significantly associated with all the dimensions of CGA investigated: poor PS (>/=2) corresponded to severe disabilities. As for the relationship of serum IL-6 with CGA variables, the strongest correlations were between IL-6 and functional status assessed by both Katz ADL (p=0.0003), IADL (p=0.0070) and nutrition (p=0.0013). Moreover, we observed an association, although not statistically significant, between functional disability (ADL and IADL) and high IL-6 levels in individuals with weight loss. IL-6 levels seem to be independently associated with all CGA variables investigated in the present study in a population of elderly cancer patients. Because the most important CGA variables, in particular functional status, have been observed to be strongly associated with survival, the present study, confirming our previously reported ones, suggests that IL-6 may be a reliable marker of disease outcome and supports the feasibility of using IL-6 as a sensitive outcome marker in studies based on novel approaches aiming at modifying age- and cancer-related biologic mechanisms.
