Cancer therapy and cachexia
Tuba Mansoor Thakir, Alice R. Wang, Amanda R. Decker-Farrell, Miriam Ferrer, Rohini N. Guin, Sam Kleeman, Llewelyn Levett, Xiang Zhao, Tobias Janowitz
Tuba Mansoor Thakir, Alice R. Wang, Amanda R. Decker-Farrell, Miriam Ferrer, Rohini N. Guin, Sam Kleeman, Llewelyn Levett, Xiang Zhao, Tobias Janowitz
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Review

Cancer therapy and cachexia

Abstract

A central challenge in cancer therapy is the effective delivery of anticancer treatments while minimizing adverse effects on patient health. The potential dual impact of therapy is clearly illustrated in cancer-associated cachexia, a multifactorial syndrome characterized by involuntary weight loss, systemic inflammation, metabolic dysregulation, and behavioral alterations such as anorexia and apathy. While cachexia research often focuses on tumor-driven mechanisms, the literature indicates that cancer therapies themselves, particularly chemotherapies and targeted treatments, can initiate or exacerbate the biological pathways driving this syndrome. Here, we explore how therapeutic interventions intersect with the pathophysiology of cachexia, focusing on key organ systems including muscle, adipose tissue, liver, heart, and brain. We highlight examples such as therapy-induced upregulation of IL-6 and growth-differentiation factor 15, both contributing to reduced nutrient intake and a negative energy balance via brain-specific mechanisms. At the level of nutrient release and organ atrophy, chemotherapies also converge with cancer progression, for example, activating NF-κB in muscle and PKA/CREB signaling in adipose tissue. By examining how treatment timing and modality align with the natural trajectory of cancer cachexia, we underscore the importance of incorporating physiological endpoints alongside tumor-centric metrics in clinical trials. Such integrative approaches may better capture therapeutic efficacy while preserving patient well-being.

Authors

Tuba Mansoor Thakir, Alice R. Wang, Amanda R. Decker-Farrell, Miriam Ferrer, Rohini N. Guin, Sam Kleeman, Llewelyn Levett, Xiang Zhao, Tobias Janowitz

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Figure 4

Dynamic effects of cancer treatment on outcome and cachexia.

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Dynamic effects of cancer treatment on outcome and cachexia. Conceptuali...
Conceptualization of the interplay between cancer treatment efficacy and toxicity (therapeutic window), disease progression, and the risk of developing cachexia. (A) Concept: Cancer and treatment have reciprocal interactions via factors x1, x2…xn and y1, y2…yn, and both affect the host system over time. The composite interactions determine how much the global body function declines. 0 indicates a nonsymptomatic precancerous state when body function is well preserved, and 1 indicates the end point when body function declines to a survival threshold. (B) Specific example: Cisplatin treatment can reduce tumor burden and consequently tumor-associated GDF-15 levels, but it can also elevate GDF-15 levels through induction of cell stress in multiple tissues and can reduce its own excretion by reducing renal filtration rates. A net increase in GDF-15 level, therefore, can increase cachexia susceptibility potentially even in the context of reduced tumor burden. (C) A pseudotime representation of body function shows that as body function declines, the therapeutic benefits diminish, and the same intervention may ultimately become detrimental because of the host effect. Therefore, an early intervention when body function is still preserved may maximize net benefits and promote survival. As discussed in “Scope and considerations,”we did not include covariables in this discussion but acknowledge that they may have an impact on body function and the interaction between cancer and treatments.