Giovanni Mantovani

Purpose The purpose of this study was to review the results of a single-center experience in the management of “closed abdomen” hyperthermic intraperitoneal chemotherapy (HIPEC) using a sophisticated technical device (EXIPER®) in the palliative setting of neoplastic ascites from peritoneal carcinomatosis in patients with advanced cancer of different primary sites. Patients and methods The study was an open, prospective, single-center, non-randomized study conducted at the Department of Medical Oncology 1, University of Cagliari, Italy, from May 2006 to October 2012. Fifteen patients with peritoneal carcinomatosis were treated with HIPEC: 5 males and 10 females (age range 51–82, median 62 years), for a total of 30 procedures (5 patients were treated more than once). Malignant ascites were from ovarian, uterine cervical, colorectal, gastric, malignant pleural mesothelioma, and unknown primary cancer. Main endpoints were increase of free interval between two consecutive procedures, progressive reduction of ascites volumes and improvement of quality of life assessed with ECOG performance status and EORTC QLQ-C30 questionnaire, and improvement of immunologic function. Results Twelve patients were completely evaluable while three patients were “lost” to follow-up. The treatment was well tolerated. The mean free interval between two consecutive drainages increased from 11.2 to 39.5 days. The mean ascites volume drained decreased from 7.8 to 1.8 l. ECOG PS improved in the majority of patients and EORTC QLQ-C30 scores in all patients as well as immunologic function. In September 2015, only one patient was still alive. Conclusions Our study shows that good results may be achieved in terms of symptom palliation and improvement of quality of life in very advanced cancer patients with MA from PC. The treatment was generally well tolerated considering the limited treatment options available for these patients.

The present review aimed at discussing the impact, pathogenesis and therapeutic approaches of muscle wasting, which is a major clinical feature of cancer-related cachexia syndrome. The pathogenesis of muscle wasting in cancer cachexia lies in a discrepancy between anabolic and catabolic pathways mediated by chronic inflammation. Effective interventions specifically aimed at hampering muscle loss and enhancing muscle function are still lacking. Promising agents include anti-inflammatory, orexigenic and anabolic drugs, alongside with nutritional supplements that influence the STAT3 and PI3K/Akt/mTOR pathways involved in muscle wasting. Personalized physical activity combined with pharmacological and nutritional support hold promise. A greater understanding of the pathogenetic processes of cancer cachexia-related muscle wasting will enable the development of an early and effective targeted mechanism-based multimodal approach.

(2015). Advances in pharmacologic strategies for cancer cachexia. Expert Opinion on Pharmacotherapy: Vol. 16, No. 14, pp. 2163-2177. doi: 10.1517/14656566.2015.1079621

Peer reviewed article authored by (Mantovani G, Madeddu C, Maccio A). Read article or submit your manuscript for publishing.

Purpose: The primary objective of the present study was to show the long lasting cardioprotective activity, at different time-points, up to 18 month-follow-up, of telmisartan in preserving the systolic function (assessed as Strain Rate-SR) in cancer patients treated with EPI both in the adjuvant and metastatic setting; the secondary objective was to confirm the correlation of the cardioprotective activity of telmisartan with a reduction of inflammation and oxidative stress induced by EPI. Methods: Phase II single blind placebo-controlled randomized trial. Sample size 50 patients per arm: based on a pre-planned interim analysis for early stopping rules, the study was discontinued for ethical reasons at 49 patients. Cardiovascular disease-free patients with cancer at different sites eligible for EPI-based treatment randomized to: telmisartan n = 25 or placebo n = 24. Echocardiography Tissue Doppler imaging (TDI) strain and strain rate was performed, serum levels of proinflammatory cytokines (IL-6, TNF-α) and oxidative stress (reactive oxygen species, ROS) were assessed at baseline, every 100 mg/m² EPI dose and at 6-, 12- and 18-month follow-up (FU). Results: Significant SR peak reduction in both arms was observed at t₂ (cumulative dose EPI 200 mg/m²) vs t₀. Conversely, at t₃, t₄, 6-, 12- and 18-month FU SR increased towards normal range in the telmisartan arm, while in the placebo arm SR remained significantly lower. Differences between SR changes in the placebo and telmisartan arm were significant from t₃ up to 18 month-FU. IL-6 and ROS increased significantly in the placebo arm at t₂ but did not change in the telmisartan arm. A significant (p < 0.05) correlation between changes of SR vs IL-6 and ROS was observed. Conclusions: Our results suggest that the protective effect of telmisartan is long lasting, probably by ensuring a permanent (at least up to 18-month FU) defense against chronic or late-onset types of anthracycline-induced cardiotoxicity.

Cachexia influences morbidity, mortality and quality of life of cancer patients at advanced stage of disease. Therefore, the knowledge of its pathophysiology is critical to develop effective therapies to be integrated in the comprehensive approach of cancer patients. Oxidative stress, unless counteracted by effective antioxidant therapies, contributes to the development of anorexia and cachexia in cancer patients. In the present review the potential role of targeting oxidative stress in the treatment of cachexia is reported. Efficacy data on the use of antioxidants in advanced cancer patients are promising. However, the optimal dosage and route of administration as well as the timing and the most effective combination are not well established. Moreover, since cachexia is a multifactorial syndrome, targeting only oxidative stress as a contributing factor would be inadequate and likely to achieve a limited clinical therapeutic benefit. According to this rationale, antioxidants should be included as essential components of a multitargeted combined treatment of cancer cachexia, which has been shown to be the most successful approach for this syndrome.

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/m2 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 t2 (cumulative dose of 200 mg/m2 of EPI) in comparison to t0. Conversely, at t3 (300 mg/m2 EPI), t4 (400 mg/m2 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 t0 (baseline). The differences between SR changes in the PLA and TEL arms were significant from 300 mg/m2 EPI (t3) up to the 12-month FU. Serum levels of IL-6 increased significantly in the PLA arm at 200 mg/m2 EPI (t2) in comparison to baseline, but remained unchanged in the TEL arm. The same trend was demonstrated for ROS levels which significantly increased at t2 vs. baseline in the PLA arm, while remained unchanged in the TEL arm. The mean change in ROS and IL-6 at t2 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 t2 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.

The purpose of this review is to provide an update of physical activity improvement as an alternative objective variable to measure treatment effects of anticachexia therapy in cancer patients. The assessment of physical activity level as an outcome measure for cachexia studies is attractive as it offers a patient-centered outcome concerned with functional status and independence. We present and review the most relevant recent clinical studies regarding the significance of physical activity in the context of the assessment of anticachexia treatment effects. Moreover, we have highlighted, on the basis of our recent phase III clinical trial on anticachexia treatment, the added value of correlating physical activity with the most common variables of cancer-related anorexia/cachexia syndrome. We believe that presently, and even more so in the near future, the consistent application of objective, patient-centered endpoints in cachexia trials, such as physical activity monitoring, may provide an additional significant and useful tool for the evaluation of outcomes of medical interventions in cancer cachexia.