Biomarker endpoints in cancer cachexia clinical trials: Systematic Review 5 of the cachexia endpoint series
Yule, Michael S.; Thompson, Joshua; Leesahatsawat, Khachonphat; Sousa, Mariana S.; Anker, Stefan D.; Arends, Jann; Balstad, Trude Rakel; Brown, Leo R.; Bye, Asta; Dajani, Olav; Fallon, Marie; Hjermstad, Marianne Jensen; Jakobsen, Gunnhild; McDonald, James; McGovern, Josh; Roeland, Eric J.; Sayers, Judith; Skipworth, Richard J.E.; Ottestad, Inger; Philips, Iain; Simpson, Melanie Rae; Solheim, Tora S; Vagnildhaug, Ola Magne; McMillan, Donald; Laird, Barry J; Dolan, Ross D.
Peer reviewed, Journal article
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https://hdl.handle.net/11250/3145103Utgivelsesdato
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Sammendrag
Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve
drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of
biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of bio-
marker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and
Cochrane (1990–2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design,
more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an end-
point. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems
based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered.
Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO:
CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included bio-
markers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions
(n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety-nine different bio-
markers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed
most often, followed by C-reactive protein (n = 22, 42.3%), interleukin-6 (n = 16, 30.8%) and tumour necrosis factor-α
(n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were
explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more.
Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased
significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body
mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory
rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of
responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as
seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the
biomarker and clinical benefit must be clarified.