Cancer-related anorexia-cachexia syndrome (CACS) is a complex syndrome characterised by progressive weight loss with depletion of host reserves of skeletal muscle and, to a lesser extent, adipose tissue, anorexia, reduced food intake, poor performance status and quality of life that often precedes death [1]. At the time of diagnosis, 80% of patients with upper gastrointestinal cancers and 60% with lung cancer have already experienced substantial weight loss [2]. The prevalence of cachexia increases from 50 to > 80% before death and in > 20% cachexia is the main cause of death [2]. CACS results from the interaction of the host and the tumour. However, its nature is incompletely understood [3] [6], including the dynamics of host response (activation of systemic inflammatory response, metabolic, immune and neuroendocrine changes) and those tumour characteristics or tumour-derived products that influence expression of the syndrome (e.g. proteolysis-inducing factor, PIF).

https://cebp.aacrjournals.org/content/cebp/15/5/1030.full.pdf

A Phase II Study with Antioxidants, Both in the Diet and Supplemented, Pharmaconutritional Support, Progestagen, and Anti-Cyclooxygenase-2 Showing Efficacy and Safety in Patients with Cancer-Related Anorexia/Cachexia and Oxidative Stress

In advanced cancer patients, the oxidative stress could take place either at the onset of disease or as a function of disease progression. To test this hypothesis, the following parameters were investigated: the erythrocyte activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), the serum activity of glutathione reductase (GR) and the serum total antioxidant status (TAS). The total antioxidant capacity of plasma LMWA was evaluated by the cyclic voltammetry methodology. We further determined the serum levels of proinflammatory cytokines (IL-6 and TNFalpha), IL-2, leptin and C-reactive protein (CRP). All of these parameters have been correlated with the most important clinical indices of patients such as Stage of disease, ECOG PS and clinical response. Eighty-two advanced stage cancer patients and 36 healthy individuals used as controls were included in the study. Our findings show that SOD activity was significantly higher in cancer patients than in controls and GPx activity was significantly lower in cancer patients than in controls. Serum values of IL-6, TNFalpha and CRP were significantly higher in patients than in controls. Serum leptin values of cancer patients were significantly lower than controls. SOD activity increased significantly from Stage II/ECOG 0-1 to Stage IV/ECOG 0-1, whereas it decreased significantly in Stage IV/ECOG 3. GPx activity decreased significantly in Stage IV/ECOG 2-3. An inverse correlation between ECOG PS and serum leptin levels was found. Serum levels of IL-2 decreased from Stage II/ECOG 0-1 to Stage IV/ECOG 2-3. A direct correlation between Stage/ECOG PS and serum levels of both IL-6 and CRP was observed. Cisplatin administration induced a significant increase of GPx after 24 hr. In conclusion, this is the first study that shows that several "biological" parameters of cancer patients such as antioxidant enzyme activity, cytokines, leptin and CRP strictly correlate with the most important clinical parameters of disease such as Stage and ECOG PS.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.10143

Quantitative evaluation of oxidative stress, chronic inflammatory indices and leptin in cancer patients: correlation with stage and performance status

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-5Dindex, and EQ-5DVAS). 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).

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Cancer-Related Anorexia/Cachexia Syndrome and Oxidative Stress: An Innovative Approach beyond Current Treatment

Purpose To determine whether zinc supplementation can accelerate the healing of mucositis and dermatitis after radiotherapy. Methods and materials In this double-blind study, patients were placed into two randomized groups (experimental and control) of 50 patients each. The groups were homogeneous with respect to medical history, tumor characteristics, and therapeutic details. The experimental group received a standard dose of a zinc supplement, and the control group was given a placebo. Results Patients in the control group developed Grade 2 mucositis and dermatitis earlier and sooner than patients in the experimental group. There was also a significant difference in the development of Grade 3 mucositis and dermatitis between the two groups. Patients in the experimental group were found to have milder mucositis and dermatitis. Zinc supplementation did not show much benefit in those patients receiving concurrent chemotherapy or make a substantial impact on weight changes. Conclusions Zinc supplementation used in conjunction with radiotherapy could postpone the development of severe mucositis and dermatitis for patients with cancers of the head and neck. Zinc supplementation can also alleviate the degree of mucositis and dermatitis. The impact of zinc on tumor growth and patient survival is under further investigation.

Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: A double-blind, randomized study

Purpose To determine the effect of oral zinc sulphate supplementation on radiation-induced oropharyngeal mucositis in patients with head-and-neck cancer. Materials and methods Thirty patients with head-and-neck cancer were randomly assigned to receive either zinc sulfate or placebo. Primary tumors were localized in the larynx in 14 patients, in the nasopharynx in 4, in the oral cavity in 4, in a salivary gland in 1, in the maxillary sinus in 1, in neck nodes (lymphoma presenting primarily) in 3 and in neck metastases from an unknown primary in 3. In the placebo group, 3 patients were excluded; 1 patient died during treatment, 1 left the study, and 1 did not come to the 6 week control visit. The patients were treated with telecobalt radiotherapy at conventional fractionation (2 Gy/fraction, five fractions weekly, for 20–35 fractions within 4–7 weeks). The median radiation dose was 6400 cGy (4000–7000 cGy). Oral mucositis was assessed by two independent physicians, experts in radiation oncology, using the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring criteria. Results In the zinc sulfate group, Grade 3–4 mucositis was not detected in any patient; Grade 0 mucositis was detected in 2, and Grade 1 in 8, and Grade 2 in 5 patients. In the placebo group, Grade 2 mucositis was detected in 4 and Grade 3 in 8 patients. We observed that the degree of mucositis in the patients in the zinc sulfate group was significantly lower than that in the placebo group ( p p p Conclusions Zinc sulfate is beneficial in decreasing the severity of radiation-induced mucositis and oral discomfort. These results should be confirmed by additional evaluation in randomized studies with a larger number of patients.

K.E. Sabitha

Papers

Oxidant and antioxidant activity changes in patients with oral cancer and treated with radiotherapy