Fatigue is a multidimensional symptom that is described in terms of perceived energy, mental capacity, and psychological status: it can impair daily functioning and lead to negative effects on ...quality of life. It is one of the most common side effects of chemotherapy and radiotherapy. In recent studies,
l-carnitine (LC) supplementation has been demonstrated to be able to improve fatigue symptoms in patients with cancer.
In the present study we tested the efficacy and safety of LC supplementation in a population of patients who had advanced cancer and developed fatigue, high blood levels of reactive oxygen species, or both. As outcome measures we evaluated fatigue and quality of life in relation to oxidative stress, nutritional status, and laboratory variables, mainly levels of reactive oxygen species, glutathione peroxidase, and proinflammatory cytokines. From March to July 2004, 12 patients who had advanced tumors (50% at stage IV) at different sites were enrolled (male-to-female ratio 2:10, mean age 60 y, range 42–73). Patients were only slightly anemic (hemoglobin 10.9 g/dL) and hemoglobin levels did not change after treatment. LC was administered orally at 6 g/d for 4 wk. All patients underwent antineoplastic treatment during LC supplementation.
Fatigue, as measured by the Multidimensional Fatigue Symptom Inventory—Short Form, decreased significantly, particularly for the General and Physical scales, and for quality of life in each subscale of quality of life in relation to oxidative stress. Nutritional variables (lean body mass and appetite) increased significantly after LC supplementation. Levels of reactive oxygen species decreased and glutathione peroxidase increased but not significantly. Proinflammatory cytokines did not change significantly.
Improvement of symptoms with respect to fatigue and quality of life in relation to oxidative stress may be explained mainly by an increase in lean body mass, which may be considered the most important nutritional or functional parameter in assessing the cachectic state of patients. In this view, fatigue with related symptoms can well be considered an important constituent of cancer-related anorexia cachexia syndrome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose: To test the efficacy and safety of an integrated treatment based on a pharmaconutritional support, antioxidants,
and drugs, all given orally, in a population of advanced cancer patients with ...cancer-related anorexia/cachexia and oxidative
stress.
Patients and Methods: An open early-phase II study was designed according to the Simon two-stage design. The integrated treatment
consisted of diet with high polyphenols content (400 mg), antioxidant treatment (300 mg/d α-lipoic acid + 2.7 g/d carbocysteine
lysine salt + 400 mg/d vitamin E + 30,000 IU/d vitamin A + 500 mg/d vitamin C), and pharmaconutritional support enriched with
2 cans per day ( n -3)-PUFA (eicosapentaenoic acid and docosahexaenoic acid), 500 mg/d medroxyprogesterone acetate, and 200 mg/d selective cyclooxygenase-2
inhibitor celecoxib. The treatment duration was 4 months. The following variables were evaluated: ( a ) clinical (Eastern Cooperative Oncology Group performance status); ( b ) nutritional lean body mass (LBM), appetite, and resting energy expenditure; ( c ) laboratory proinflammatory cytokines and leptin, reactive oxygen species (ROS) and antioxidant enzymes; ( d ) quality of life (European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5D, and MFSI-SF).
Results: From July 2002 to January 2005, 44 patients were enrolled. Of these, 39 completed the treatment and were assessable.
Body weight increased significantly from baseline as did LBM and appetite. There was an important decrease of proinflammatory
cytokines interleukin-6 (IL-6) and tumor necrosis factor-α, and a negative relationship worthy of note was only found between
LBM and IL-6 changes. As for quality of life evaluation, there was a marked improvement in the European Organization for Research
and Treatment of Cancer QLQ-C30, Euro QL-5D VAS , and multidimensional fatigue symptom inventory-short form scores. At the end of the study, 22 of the 39 patients were “responders”
or “high responders.” The minimum required was 21; therefore, the treatment was effective and more importantly was shown to
be safe.
Conclusion: The efficacy and safety of the treatment have been shown by the study; therefore, a randomized phase III study
is warranted. (Cancer Epidemiol Biomarkers Prev 2006;15(5):1030–4)
Objective: Cancer-related anorexia/cachexia syndrome and oxidative stress play a key role in the progression and outcome of
neoplastic disease. Patients and Methods: On the basis of our previously ...published studies and clinical experience, we have
developed an innovative approach consisting of diet with high polyphenol content (400 mg), p.o. pharmaconutritional support
enriched with n − 3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) 2 cans (237 mL each) per day, medroxiprogesterone acetate
500 mg/d, antioxidant treatment with α-lipoic acid 300 mg/d plus carbocysteine lysine salt 2.7 g/d plus vitamin E 400 mg/d
plus vitamin A 30,000 IU/d plus vitamin C 500 mg/d, and selective cyclooxygenase-2 inhibitor Celecoxib 200 mg/d. The treatment
is administered for 16 weeks. The following variables are evaluated: ( a ) clinical variables (stage and Eastern Cooperative Oncology Group performance status); ( b ) nutritional variables (lean body mass, appetite, and resting energy expenditure); ( c ) laboratory variables (serum levels of proinflammatory cytokines, C-reactive protein, and leptin and blood levels of reactive
oxygen species and antioxidant enzymes); and ( d ) quality of life variables (European Organization for Research and Treatment of Cancer QLQ-C30, EQ-5D index , and EQ-5D VAS ). A phase II nonrandomized study has been designed to enroll 40 patients with advanced cancer at different sites with symptoms
of cancer-related anorexia/cachexia syndrome and oxidative stress. Results: As of January 2004, 28 patients have been enrolled:
25 patients were evaluable and 14 of them have completed the treatment (20 patients have completed 2 months of treatment).
As for clinical response, five patients improved, three patients remained unchanged, and six patients worsened. The Eastern
Cooperative Oncology Group performance status (grade) 1 remained unchanged. As for nutritional/functional variables, the lean
body mass increased significantly at 2 and 4 months. As for laboratory variables, reactive oxygen species decreased significantly
and proinflammatory cytokines interleukin-6 and tumor necrosis factor-α decreased significantly. As for quality of life, it
comprehensively improved after treatment. Conclusions: The treatment has been shown to be effective for clinical response,
increase of lean body mass, decrease of reactive oxygen species and proinflammatory cytokines, and improvement of quality
of life. The treatment has been shown to be safe with good compliance of patients. The study is in progress (14 further patients
will be included).
This study assessed in a wide population of advanced cancer patients the biological parameters relevant to cancer cachexia, such as serum levels of proinflammatory cytokines (IL-1beta, IL-6, ...TNFalpha), IL-2, acute-phase proteins (C-reactive protein and fibrinogen), leptin, and relevant to oxidative stress (OS), such as ROS, body antioxidant enzymes GPx and SOD. We also studied the ability of effective antioxidant agents alpha-lipoic acid (ALA), N-acetyl cysteine (NAC), and amifostine (AMI) added into culture to induce lymphocyte progression through the cell cycle, namely to enter into S phase. Additionally, we assessed the most significant clinical indexes of nutritional status such as body mass index and disease progression such as stage and ECOG-PS in the same cancer patient population. Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs isolated from 120 cancer patients and 60 controls, with or without ALA, NAC, or AMI, was studied. The biological parameters relevant to cancer cachexia and OS were also studied. The addition of antioxidants ALA, NAC and AMI, enhanced significantly the progression through the cell cycle, namely from G0/G1 to S phase, of PBMCs isolated from cancer patients (+132%, +150% and +141%, respectively). The percentage of PHA-stimulated PBMCs of cancer patients entering S phase, which was significantly lower than that of controls, increased significantly to more than physiological level after coculture with antioxidants. ROS levels were significantly higher and GPx and SOD activities significantly lower in cancer patients than controls. Serum levels of IL-1 beta, IL-6, and TNFalpha were significantly higher and serum levels of IL-2 and leptin significantly lower in cancer patients than controls. Serum levels of C-reactive protein and fibrinogen were significantly higher in cancer patients than controls. A significant correlation was found in laboratory parameters only between serum levels of leptin and body mass index. Patients with advanced cancer thus exhibit both a high-grade OS and a chronic inflammatory condition. Antioxidant agents ALA, NAC, and AMI enhanced significantly the PBMCs progression through the cell cycle, thus providing evidence of their potential role in the functional restoration of the immune system in advanced cancer patients. Our data warrant further investigation with adequate clinical trials.
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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
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
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.
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 (IL) 1alpha, IL-6, tumor necrosis factor (TNF) alpha and interferon (IFN) 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. To elucidate this we studied the relationship between total serum leptin and serum cytokines IL-1alpha, IL-6, TNFalpha as well as the production of leptin and cytokines by peripheral blood mononuclear cells (PBMC) isolated from cancer patients. Sixteen advanced cancer patients (mainly stage IV) with tumors at different sites were included in the study. The serum levels of leptin in cancer patients were significantly lower than those of healthy individuals at all times (7 a.m., noon, 3 p.m.). No significant differences were found in circadian rhythm between patients and controls. Serum levels of IL-1alpha, IL-6, and TNFalpha were significantly higher in cancer patients than in healthy individuals. An inverse correlation between serum levels of leptin and IL-6 was found in cancer patients. The production in culture of leptin by unstimulated PBMCs and those stimulated by phytohemagglutinin M or by phorbol myristate acetate isolated from cancer patients was very low; no differences were observed in comparison with leptin production by PBMCs from healthy individuals.
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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
Abstract only
e13009
Background: Epidermal growth factor (EGF) plays an important role in carcinogenesis. An adenine (A) to guanine (G) single nucleotide polymorphism at position 61 in the ...5'-untranslated region (5'-UTR) of the EGF gene has been found to be associated with levels of EGF production and contribute to the risk of glioma. However, published data are contradictory. EGF +61G/A polymorphism may contribute to the risk of glioma in different ethnic group. Patients with glioma and GG genotype have been reported to have a risk of poorer otucome than patients with AA genotype. Purpose of this study is to investigate the potential role of this polymorphism in cancer progression and its role as predictive marker of outcome in glioma caucasian patients. Methods: EGF 61A/G polymorphism (rs4444903) was analyzed in glioma patients and was determined by means of Polymerase Chain Reaction and Direct Sequencing method (GenBank reference sequence-accession no. AC005509) from blood samples. Association of this genetic polymorphism with clinical and pathological data of patients was evaluated. Results: We investigated EGF +61G/A polymorphism in 24 glioma patients . EGF +61G allele has been found in 67% of glioma patients (25% G/G genotype and 42% A/G genotype). In astrocytomas, EGF +61G allele represents a 83% frequency; in glioblastomas and in oligodendrogliomas, EGF +61G allele frequency represents respectively 71% and 50%. In WHO IV gliomas, the EGF +61G allele represents a 63% frequency, (27% G/G and 36% A/G ), in WHO III gliomas a 77% frequency (33% G/G and 44% A/G ) and in WHO II gliomas a 50% frequency (100% A/G ). Median PFS of glioblastoma patients was 9 months. 83% of glioblastoma patients with a relapsing disease showed the G/G and A/G genotype. No difference was detected in the others histotypes. Conclusions: Our data conferm previous studies which reported G allele as a risk factor for glioma in Caucasian. G/A and G/G genotypes seem to be more rappresentative in high grade gliomas . Despite limited number of patients, our study supports the predictive role of EGF 61 A/G polymorphism in GBM. Additional large studies are warranted to confirm the role of EGF polymorphism as indipendent prognostic factor in glioma.
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
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