Cancer Cachexia: It’s Time for More Clinical Trials

Abstract

Cancer cachexia (CC) is a multifactorial paraneoplastic syndrome characterized by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, accounting for at least 20% of deaths in neoplastic patients. CC significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of CC and the principal cause of function impairment, fatigue and respiratory complications, mainly related to a hyperactivation of muscle proteolytic pathways. Most current therapeutic strategies to counteract CC have proven to be only partially effective. In the last decade, the correction of anorexia, the inhibition of catabolic processes and the stimulation of anabolic pathways in muscle have been attempted pharmacologically with encouraging results in animal models and through preliminary clinical trials. However, data in the clinical setting are still scanty and non definitive. It is time to start prospective, randomized, controlled trials to evaluate which drugs are effective in counteracting the loss of lean of muscle mass and in improving nutritional status and quality of life in patients affected by cancer-related cachexia.

Randomized Phase III Clinical Trial of Five Different Arms of Treatment in 332 Patients with Cancer Cachexia

“…The predominant features of CACS, that is, progressive loss of muscle mass and function, have been shown to be only minimally affected by the nutritional or pharmacologic tools currently available. Conversely, a combination of dietary, nutritional, and pharmacologic approaches to normalize the metabolic environment may have the potential to reverse CACS and improve the associated symptoms that affect QoL [31,32].…”

Molekulare und metabolische Komponenten der Tumorkachexie

“…Mit fortschreitendem Gewichtsverlust verschlechtern sich die Lebensqualität der Patienten, die Prognosen für die Therapie und die Heilungschancen dramatisch. Diese Auszehrung ist am stärksten ausgeprägt bei Patienten mit Pankreas-, Lungen-und Kolonkarzinomen [7,25].…”

“…weißen Fettzellen (Adipozyten), undifferenzierten Fettvorläuferzellen sowie Makrophagen, glatten Muskelzellen, Endothelzellen und Fibroblasten zusammen [13]. Der dramatische Verlust dieses Gewebes ist wesentliche Grundlage des energiedefizienten Stoffwechsels im Stadium der Tumorkachexie [7,25]. Im Gegensatz zu den weißen Fettzellen, die wesentlich für die Fett-/Energiespeicherung verantwortlich sind, zeigen sog.…”

Skeletal muscle of gastric cancer patients expresses genes involved in muscle regeneration

“…The loss of muscle protein, defined as muscle catabolism, occurs due to an imbalance between the rates of muscle protein synthesis and breakdown (1). In recent years, numerous studies have contributed to our understanding of the mechanisms underlying the increase of skeletal muscle protein breakdown in cancer cachexia and to the clarification of the relative contribution of different proteolytic pathways (2,3). Four major proteolytic systems exist in the skeletal muscle: The endosome-lysosome system that relies on the activity of acidic proteases, the caspases, the calpains, and the ubiquitinproteasome system (2,3).…”

“…In recent years, numerous studies have contributed to our understanding of the mechanisms underlying the increase of skeletal muscle protein breakdown in cancer cachexia and to the clarification of the relative contribution of different proteolytic pathways (2,3). Four major proteolytic systems exist in the skeletal muscle: The endosome-lysosome system that relies on the activity of acidic proteases, the caspases, the calpains, and the ubiquitinproteasome system (2,3). The bulk of muscle proteins (50-70%) exists in the actomyosin complexes and myofibrils, and in different catabolic conditions, contractile proteins in these complexes are degraded by the ubiquitin-proteasome system (4).…”