Abstract Objective In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative ...stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-α, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF). Methods All patients were given as basic treatment polyphenols plus antioxidant agents α-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) l -carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus l -carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients. Results By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes. Conclusion The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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).
Adjuvant endocrine therapy is an integral component of care for endocrine-dependent breast cancer. The aim of this type of therapy is to counteract the production and the action of estrogens. The ...ovary is the primary site of estrogen production in premenopausal women, whereas, in postmenopausal women, the main source of estrogens is adipose tissue. Therefore, ovarian function suppression is an effective adjuvant strategy in premenopausal estrogen-dependent breast cancer. Similarly, the inhibition of estrogen action at the receptor site by tamoxifen has proven to be effective. To date, international consensus statements recommend tamoxifen (20 mg/day) for five years as the standard adjuvant endocrine therapy for premenopausal women. It should be noted that tamoxifen is a potent inducer of ovarian function and consequent hyperestrogenism in premenopausal women. In the present study, we report two cases of ovarian cyst formation with very high estrogen levels and endometrial hyperplasia during the administration of tamoxifen alone as adjuvant treatment for estrogen receptor-positive breast cancer in premenopausal women. These cases suggest that in young premenopausal patients with estrogen-dependent breast cancer, ovarian suppression is an essential prerequisite for an adjuvant endocrine therapy with tamoxifen. In this context, luteinizing hormone-releasing hormone agonist treatment by suppressing effective ovarian function may lead to a hypoestrogenic status that may positively impact breast cancer prognosis and prevent the effects of tamoxifen at the gynecological level. It is important to reconsider the action of tamoxifen on ovarian function and include these specific effects of tamoxifen in the informed consent of premenopausal patients who are candidates for tamoxifen alone as adjuvant endocrine treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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
Weight gain and obesity are among the most important risk factors for post‐menopausal oestrogen‐dependent breast cancer (EDBC). Weight gain is associated with oxidative stress, which in turn promotes ...breast cancer progression. We carried out a prospective study in 216 consecutive post‐menopausal breast cancer patients aiming to examine the correlations between traditional prognostic factors (tumour size, T, nodal, N, grading, G, and metastasis status, M), and body mass index (BMI), leptin, pro‐inflammatory cytokines (Interleukin, IL,‐6 and tumour necrosis factor‐alpha, TNF‐α), and oxidative stress (reactive oxygen species, ROS, glutathione peroxidase, GPx, superoxide dismutase, SOD) among patients with oestrogen receptor (ER)+ and ER− breast cancers. Distribution of T, N and M categories did not differ between ER+ and ER− breast cancer patients. ER− patients showed a higher incidence of G3 tumours. Weight, BMI, leptin, IL‐6 and ROS were higher in ER+ compared with ER− patients. Among ER+ patients, BMI, leptin, IL‐6 and ROS correlated with T and M. Leptin, IL‐6 and ROS were positively correlated also with N. Among ER− patients, BMI and leptin did not correlate with any of prognostic parameters, whereas a positive correlation between IL‐6, ROS and M was found. Multivariate regression analysis showed that BMI, leptin, IL‐6 and ROS were predictive for T, N and M in ER+ patients. Weight gain, inflammation and oxidative stress are involved in EDBC prognosis. Their modulation through antidiabetic, anti‐inflammatory and antioxidants drugs combined with endocrine therapy may constitute a targeted approach in post‐menopausal EDBC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Objectives Gynecological neoplastic disease progression is characterized by specific energy metabolism alterations and by symptoms including fatigue, anorexia, nausea, anemia, and ...immunodepression, which result in a cachexia syndrome and a marked decrease in patient quality of life (QoL). Therapeutic protocols associated with appropriate and effective psychological and social support systems are essential to counteract the symptoms of neoplastic disease in incurable patients. Methods A phase III randomized study was performed to establish the most effective and safest treatment to improve the key symptoms in advanced gynecological cancer patients, i.e. , lean body mass (LBM), resting energy expenditure (REE), fatigue, and QoL. In addition, the impact of the treatment arms on the main metabolic and inflammatory parameters, including C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, leptin, reactive oxygen species (ROS), and glutathione peroxidase, was evaluated. The change in the Glasgow Prognostic Score (GPS) during treatment was also assessed. A total of 104 advanced-stage gynecological cancer patients were enrolled and randomly assigned to receive either megestrol acetate (MA) plus l -carnitine, celecoxib, and antioxidants (arm 1) or MA alone (arm 2). The treatment duration was 4 months. Results The combination arm was more effective than arm 2 with respect to LBM, REE, fatigue, and global QoL. As for the secondary efficacy endpoints, patient appetite increased, and ECOG PS decreased significantly in both arms. The inflammation and oxidative stress parameters IL-6, TNF-α, CRP, and ROS decreased significantly in arm 1, while no significant change was observed in arm 2. Conclusions The combined treatment improved both immunometabolic alterations and patient QoL. Multimodality therapies for cachexia ideally should be introduced within a context of “best supportive care” that includes optimal symptom management and careful psychosocial counseling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Introduction: Cancer cachexia is a severe inflammatory metabolic syndrome accounting for fatigue, an impairment of normal activities and, eventually, death. The loss of muscle mass associated with ...body weight loss is the main feature of this syndrome.
Areas covered: The present review aims to describe the advances in the pharmacological approaches for cancer cachexia, highlighting the impact on weight loss, muscle wasting and related outcomes.
Expert opinion: Among the pharmacological agents, attention should yet be given to the currently most widely studied drugs, such as progestogens and NSAIDs. Emerging drugs, such as ghrelin and selective androgen receptor modulators, have obtained promising results in recent randomized clinical trials. Larger sample sizes and more robust data on the effectiveness of anti-cytokine agents are needed. Any pharmacological approach to counteract cancer cachexia should always be associated with an adequate caloric intake, obtained by diet or through enteral or parenteral supplementation, if indicated. Finally, we can currently state that a combined approach that simultaneously targets the fundamental pathways involved in the pathogenesis of cancer cachexia is likely to be the most effective in terms of improvements in body weight as well as muscle wasting, function, physical performance and quality of life.
Advanced‐stage cancer patients often suffer from anemia that closely resembles the anemia of chronic inflammatory diseases characterized by specific changes in iron homeostasis and absorption. i.v. ...iron improves the efficacy of recombinant human erythropoietin (rHuEPO) in anemic cancer patients undergoing chemotherapy. We report the results of an open‐label, randomized, prospective trial aimed at testing the efficacy and safety of treatment with oral lactoferrin versus i.v. iron, both combined with rHuEPO, for the treatment of anemia in a population of 148 advanced cancer patients undergoing chemotherapy. All patients received s.c. rHuEPO‐β, 30,000 UI once weekly for 12 weeks, and were randomly assigned to ferric gluconate (125 mg i.v. weekly) or lactoferrin (200 mg/day). Both arms showed a significant hemoglobin increase. No difference in the mean hemoglobin increase or the hematopoietic response, time to hematopoietic response, or mean change in serum iron, C‐reactive protein, or erythrocyte sedimentation rate were observed between arms. In contrast, ferritin decreased in the lactoferrin arm whereas it increased in the i.v. iron arm. In conclusion, these results show similar efficacy for oral lactoferrin and for i.v. iron, combined with rHuEPO, for the treatment of anemia in advanced cancer patients undergoing chemotherapy.
Reported are the results of an open‐label, randomized, prospective trial aimed at testing the efficacy and safety of treatment with oral lactoferrin versus i.v. iron, both combined with recombinant human erythropoietin, for the treatment of anemia in a population of advanced cancer patients undergoing chemotherapy.
Obesity is considered the most important risk and prognostic factor for estrogen-dependent breast cancer in postmenopausal women. Adipokines, in particular leptin, are at the center of the ...etiopathogenetic mechanisms by which obesity and related metabolic disorders influence breast cancer risk and its prognosis. The present prospective observational study aims to investigate the relationship between body mass index (BMI), serum levels of leptin and proinflammatory cytokines, and breast cancer prognostic factors. In the study, 98 postmenopausal and 82 premenopausal patients with ER-positive breast cancer participated. During the same study period, 221 control subjects were simultaneously recruited. Women underwent baseline measurements pre-operatively, before any surgical and systemic treatments. Pathologic characteristics of tumors were abstracted from pathology reports. Leptin and proinflammatory cytokines were assayed in stored fasting blood specimens. In postmenopausal breast cancer patients, BMI, leptin, and interleukin-6 significantly correlated with pathological tumor classification (pT) and TNM stage. Multivariate regression analysis showed that BMI and leptin, but not interleukin-6, were independent predictive variables of pT and TNM stage. Our results seem to suggest a twofold role of leptin in the etiopathogenesis of postmenopausal estrogen-positive breast cancer. Indeed, leptin reflects the total amount of fat mass, which correlates to aromatase activity and subsequent estrogens levels. Further studies are warranted to clarify the role of leptin and interleukin-6 in breast carcinogenesis and identify new therapeutic options, beyond the use of aromatase inhibitors, acting selectively on adipokine-driven pathways.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic ...value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population.
A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study. Genomic DNA was isolated from formalin-fixed, paraffin-embedded primary tumour tissue samples of CRC patients and screened for mutations in RAS and BRAF genes, using pyrosequencing assays, and in PIK3CA gene, using automated DNA sequencing assays.
Overall, mutation rates were 35.6 % for KRAS, 4.1 % for NRAS, and 2.1 % for BRAF. Among available DNA samples, 114/796 (14.3 %) primary CRCs were found to carry a mutation in the PIK3CA gene. In this subset of patients analysed in all four genes, a pathogenetic mutation of at least one gene was discovered in about half (378/796; 47.5 %) of CRC cases. A mutated BRAF gene was found to steadily act as a negative prognostic factor for either time to progression as metastatic disease (from detection of primary CRC to diagnosis of first distant metastasis; p = 0.009) or partial survival (from diagnosis of advanced disease to the time of death or last control; p = 0.006) or overall survival (p < 0.001). No significant impact on prognosis was observed for mutated KRAS, NRAS, and PIK3CA genes or combined RAS mutations (all RAS).
Our study defines both prevalence and prognostic role of main activated oncogenes in a population-based large collection of CRC patients.
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