Cancer, cachexia, prostanoids, and NSAIDs

Abstract

It is a major medical challenge to provide treatments that can help patients with advanced cancer – to relieve pain, remedy functional impairment, and counteract wasting and fatigue. Cachexia, the crucial feature of which is muscle wasting, with or without loss of fat, and with associated weakness, disability, and reduced quality of life, affects a majority of the patients with advanced cancer and has been estimated to be the direct cause of death in a substantial proportion of the cases. Unfortunately, therapeutic options are limited. Progestins may increase appetite and body weight, and they, to some extent also glucocorticoids, are in clinical use, but they do not counteract loss of muscle mass [1]. New approaches are needed. While the pathophysiology of cancer cachexia is not fully understood, research over the past two decades has yielded insights into some of the underlying mechanisms [2,3]. This research has, in particular, established the role of systemic infl ammation in cachexia and the involvement of cytokines and other pro-infl ammatory mediators, identifi ed certain tumor-derived cachexia-inducing factors, and characterized the resultant metabolic dysregulation which leads to proteolysis and lipolysis and thereby loss of skeletal muscle mass and fat depletion. This knowledge may bring clues to better therapies. However, while numerous strategies have been attempted in cancer cachexia and many are currently being investigated [1,4], no satisfactory treatment has so far been established. Therefore, both more basic research and clinical trials are needed to develop new strategies and to exploit the information that already exists. One therapeutic principle that has been attempted in patients with advanced cancer and cachexia is the use of non-steroid anti-infl ammatory drugs (NSAIDs). These agents are inhibitors of the cyclooxygenases (COX-1 and COX-2), i.e. the enzymes that are rate-determining in the synthesis of prostaglandins and other prostanoids from arachidonic acid [5]. The prostaglandins mediate a large number of cellular effects involved in many physiological regulations and pathologic conditions [6]. A notable role of prostaglandins is their important participation in various types of infl ammation. Activation of cyclooxygenases, particularly the inducible form, COX-2, is triggered by cell damage, various pro-infl ammatory cytokines, and possibly tumor-derived factors. This increases the levels of prostaglandins, which in turn act in concert with cytokines, thus participating in fundamental infl ammation-promoting synergistic loops and networks. Consequently, inhibition of cyclooxygenases is an important and well-established pharmacological mechanism exploited in the treatment of infl ammatory disease. Furthermore, with the emerging realization that infl ammation is a crucial factor in the pathophysiology of cancer cachexia [2,3], it has been logical to try NSAIDs in this condition. In this issue of Acta Oncologica , Solheim and colleagues [7] have reviewed clinical studies of the effects of NSAIDs in cancer cachexia. They fi nd that, despite great heterogeneity in terms of study design, number of patients, type of cancer, clinical parameters, and defi nition of effect criteria, the studies that were reviewed, taken together, support the notion that NSAIDs can have benefi cial effects in cachectic cancer patients. From a large number of retrieved articles, 13 studies were included in the review. Due to the heterogeneity of the studies, a formal meta-analysis was not appropriate, and Solheim et al. made a qualitative analysis and synthesis of the data