Biological Rationale of Medical Treatment of Cancer Cachexia

Recently, many authors have investigated the different pathogenetic events responsible for the clinical behaviour of cancer cachexia, and suggested a role for both tumour cells and immuno-mediated responses to tumour growth, as important events in the pathogenesis of the syndrome [1, 7, 9-41]. Although the main pathogenetic events are not fully understood and the relationship between tumour factors and host inflammatory cytokines still remains undefined, a role of different tumour products and an immuno-mediated action of the monocyte-macrophage system seem to be involved in the pathogenesis of cancer cachexia (Fig. 1). Besides the speculative value of the biological knowledge about the role of host and tumour cytokines, the efforts of clinical researchers have been addressing the possibility of down-regulating the pro-cachectic action of cytokines, favouring a control of the clinical manifestations of the syndrome. To this end, progestagens and corticos-teroids (and also non-steroidal anti-inflammatory drugs, eicosapentaenoic acid, melatonin and thalidomide) have been evaluated and proposed as active options in the treatment of cachexia-related

TUMOUR

Aetiological approach

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Fig. 1. Main pathogenetic events and sites of action of therapeutic options

symptoms [24-26,42-57]. Two considerations can be made, coupling the biological dimension and the clinical approach:

- Besides representing a pathogenetic treatment, a treatment addressed towards one or more steps in the pathogenesis of the clinical syndrome might also be considered a kind of'target treatment' in palliative care [42-44,46,47]

- The different sites of action of the different molecules might represent the starting point for a poly-pharmacotherapy against different steps in the same cascade [55-57].

The concept of a treatment designed on the basis of the biological characterisation of the dis ease represents one of the main topics of modern oncology, and some different models of clinical research and clinical practice support the activity and effectiveness of such an approach in the treatment of solid and haematological cancers [58-66]. There are two fields that might represent an interesting dimension in the pathogenetic approach to the palliative treatment of cancer cachexia:

- The use of biological markers to select the patients with the highest probability of response to the treatment (predictive value of the marker)

- The use of biological markers as surrogate endpoints of response.

This kind of approach has recently been evaluated in clinical research, and some preliminary results seem promising, but it would be hasty to state that the treatment of cancer cachexia as a 'target approach' is possible [57, 67]. Indeed, the reasons limiting a 'target approach' are various, and not well known. Besides the role of cytokines (interleukin 1, interleukin 6, interferon gamma and tumour necrosis factor alpha) in the patho-genesis of cachexia, some other mechanisms might play a pathogenetic role together with or instead of the cytokine cascade, favouring a low activity of an 'anti-cytokines' approach, or a mechanism of 'escape' in some patients [1,68]. However, the possible variables occurring in the 'cytokine-mediat-ed' anorexia-cachexia syndrome probably represent one of the main reasons supporting a target approach. An improvement in clinical results might be achievable by selecting patients using biological predictive factors of response, when we are able to detect biological markers in daily clinical practice [31-39,42-44].

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