Oncological and Survival Endpoints in Cancer Cachexia Clinical Trials: Systematic Review 6 of the Cachexia Endpoints Series

Cancer Cachexia Endpoints Working Group; Olav Dajani; Iain Philips; Ester Kristine  Størkson; Trude Rakel Balstad; Leo R Brown; Asta Bye; Ross Dolan; Christine Greil; Marianne Hjermstad; Gunnhild Jakobsen; Stein Kaasa; James McDonald; Inger Ottestad; Judith Sayers; Melanie Simpson; Mariana S Sousa; Ola Magne Vagnildhaug; Michael S Yule; Barry J A Laird; Richard J E Skipworth; Tora S Solheim; Mark Stares; Jann Arends

doi:10.1002/jcsm.13756

Oncological and Survival Endpoints in Cancer Cachexia Clinical Trials: Systematic Review 6 of the Cachexia Endpoints Series

Cancer Cachexia Endpoints Working Group, Olav Dajani, Iain Philips, Ester Kristine Størkson, Trude Rakel Balstad, Leo R Brown, Asta Bye, Ross Dolan, Christine Greil, Marianne Hjermstad, Gunnhild Jakobsen, Stein Kaasa, James McDonald, Inger Ottestad, Judith Sayers, Melanie Simpson, Mariana S Sousa, Ola Magne Vagnildhaug, Michael S Yule, Barry J A LairdRichard J E Skipworth, Tora S Solheim, Mark Stares, Jann Arends^*

^*Corresponding author for this work

Deanery of Molecular, Genetic and Population Health Sciences

Research output: Contribution to journal › Review article › peer-review

Abstract

Backgrounds

In patients receiving anti-cancer treatment, cachexia results in poorer oncological

outcomes. However, there is limited understanding and no systematic review of

oncological endpoints in cancer cachexia (CC) trials. This review examines oncological

endpoints in CC clinical trials.

Methods

An electronic literature search of MEDLINE, Embase and Cochrane databases (1990

to 2023) was performed. Eligibility criteria comprised: participants >18 years old;

controlled design; >40 participants; and a cachexia intervention for >14 days. Trials

reporting at least one oncological endpoint were selected for analysis. Data extraction

was performed using Covidence and followed PRISMA guidelines and the review was

registered (PROSPERO CRD42022276710).

Results

Fifty-seven trials were eligible, totalling 9,743 patients (median: 107, IQR: 173).

Twenty-six (46%) trials focussed on a single tumour site: eight in lung, six in

pancreatic, six in head and neck and six in GI cancers. Forty-two (74%) studies

included patients with stage III/IV disease and 41 (70%) included patients receiving

palliative anti-cancer treatment. Ten studies (18%) involved patients on curative

treatment. Twenty-eight (49%) studies used pharmacological interventions, 29 (50%)

used oral nutrition, and two (4%) used enteral or parenteral nutrition.

Reported oncological endpoints included: overall survival (OS, n=46 trials), progression

free survival (PFS, n=7), duration of response (DR, n=1), response rate (RR, n=9),

completion of treatment (TC, n=11) and toxicity/adverse events (AE, n=42). Median OS

differed widely from 60 to 3,468 days. Of the 50 46 studies, only three reported a

significant positive effect on survival. Seven trials showed a difference in AE, four in

TC, one in PFS and one in RR. Reported significances were unreliable due to missing

adjustments for extensive multiple testing. Only three of the six trials using OS as the

primary endpoint, reported pre-trial sample size calculations, but only one recruited the

planned number of patients.

Conclusion

In CC trials, oncological endpoints were mostly secondary and only few significant

findings have been reported. Due to heterogeneity in oncological settings, nutritional

and metabolic status and interventions, firm conclusions about CC treatment are not

possible. OS and AE are relevant endpoints, but future trials targeting clinically

meaningul hazard ratios will required more homogeneous patient cohorts, adequate

pre-trial power analyses, and adherence to statistical testing standards.

Original language	English
Article number	e13756
Journal	Journal of Cachexia, Sarcopenia and Muscle
Volume	16
Issue number	2
Early online date	10 Mar 2025
DOIs	https://doi.org/10.1002/jcsm.13756
Publication status	Published - 4 Apr 2025

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J cachexia sarcopenia muscle - 2025 - Dajani - Oncological and Survival Endpoints in Cancer Cachexia Clinical Trials Final published version, 2.15 MBLicence: Creative Commons: Attribution (CC-BY)

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Cancer Cachexia Endpoints Working Group, Dajani, O., Philips, I., Størkson, E. K., Balstad, T. R., Brown, L. R., Bye, A., Dolan, R., Greil, C., Hjermstad, M., Jakobsen, G., Kaasa, S., McDonald, J., Ottestad, I., Sayers, J., Simpson, M., Sousa, M. S., Vagnildhaug, O. M., Yule, M. S., ... Arends, J. (2025). Oncological and Survival Endpoints in Cancer Cachexia Clinical Trials: Systematic Review 6 of the Cachexia Endpoints Series. Journal of Cachexia, Sarcopenia and Muscle, 16(2), Article e13756. https://doi.org/10.1002/jcsm.13756

@article{9fee677b9b114ebea6250814ae8574e1,

title = "Oncological and Survival Endpoints in Cancer Cachexia Clinical Trials: Systematic Review 6 of the Cachexia Endpoints Series",

abstract = "BackgroundsIn patients receiving anti-cancer treatment, cachexia results in poorer oncologicaloutcomes. However, there is limited understanding and no systematic review ofoncological endpoints in cancer cachexia (CC) trials. This review examines oncologicalendpoints in CC clinical trials.MethodsAn electronic literature search of MEDLINE, Embase and Cochrane databases (1990to 2023) was performed. Eligibility criteria comprised: participants >18 years old;controlled design; >40 participants; and a cachexia intervention for >14 days. Trialsreporting at least one oncological endpoint were selected for analysis. Data extractionwas performed using Covidence and followed PRISMA guidelines and the review wasregistered (PROSPERO CRD42022276710).ResultsFifty-seven trials were eligible, totalling 9,743 patients (median: 107, IQR: 173).Twenty-six (46%) trials focussed on a single tumour site: eight in lung, six inpancreatic, six in head and neck and six in GI cancers. Forty-two (74%) studiesincluded patients with stage III/IV disease and 41 (70%) included patients receivingpalliative anti-cancer treatment. Ten studies (18%) involved patients on curativetreatment. Twenty-eight (49%) studies used pharmacological interventions, 29 (50%)used oral nutrition, and two (4%) used enteral or parenteral nutrition.Reported oncological endpoints included: overall survival (OS, n=46 trials), progressionfree survival (PFS, n=7), duration of response (DR, n=1), response rate (RR, n=9),completion of treatment (TC, n=11) and toxicity/adverse events (AE, n=42). Median OSdiffered widely from 60 to 3,468 days. Of the 50 46 studies, only three reported asignificant positive effect on survival. Seven trials showed a difference in AE, four inTC, one in PFS and one in RR. Reported significances were unreliable due to missingadjustments for extensive multiple testing. Only three of the six trials using OS as theprimary endpoint, reported pre-trial sample size calculations, but only one recruited theplanned number of patients.ConclusionIn CC trials, oncological endpoints were mostly secondary and only few significantfindings have been reported. Due to heterogeneity in oncological settings, nutritionaland metabolic status and interventions, firm conclusions about CC treatment are notpossible. OS and AE are relevant endpoints, but future trials targeting clinicallymeaningul hazard ratios will required more homogeneous patient cohorts, adequatepre-trial power analyses, and adherence to statistical testing standards.",

author = "{Cancer Cachexia Endpoints Working Group} and Olav Dajani and Iain Philips and St{\o}rkson, {Ester Kristine} and Balstad, {Trude Rakel} and Brown, {Leo R} and Asta Bye and Ross Dolan and Christine Greil and Marianne Hjermstad and Gunnhild Jakobsen and Stein Kaasa and James McDonald and Inger Ottestad and Judith Sayers and Melanie Simpson and Sousa, {Mariana S} and Vagnildhaug, {Ola Magne} and Yule, {Michael S} and Laird, {Barry J A} and Skipworth, {Richard J E} and Solheim, {Tora S} and Mark Stares and Jann Arends",

year = "2025",

month = apr,

day = "4",

doi = "10.1002/jcsm.13756",

language = "English",

volume = "16",

journal = "Journal of Cachexia, Sarcopenia and Muscle",

issn = "2190-5991",

publisher = "Wiley-Blackwell",

number = "2",

}

Cancer Cachexia Endpoints Working Group, Dajani, O, Philips, I, Størkson, EK, Balstad, TR, Brown, LR, Bye, A, Dolan, R, Greil, C, Hjermstad, M, Jakobsen, G, Kaasa, S, McDonald, J, Ottestad, I, Sayers, J, Simpson, M, Sousa, MS, Vagnildhaug, OM, Yule, MS, Laird, BJA , Skipworth, RJE, Solheim, TS, Stares, M & Arends, J 2025, 'Oncological and Survival Endpoints in Cancer Cachexia Clinical Trials: Systematic Review 6 of the Cachexia Endpoints Series', Journal of Cachexia, Sarcopenia and Muscle, vol. 16, no. 2, e13756. https://doi.org/10.1002/jcsm.13756

TY - JOUR

T1 - Oncological and Survival Endpoints in Cancer Cachexia Clinical Trials

T2 - Systematic Review 6 of the Cachexia Endpoints Series

AU - Cancer Cachexia Endpoints Working Group

AU - Dajani, Olav

AU - Philips, Iain

AU - Størkson, Ester Kristine

AU - Balstad, Trude Rakel

AU - Brown, Leo R

AU - Bye, Asta

AU - Dolan, Ross

AU - Greil, Christine

AU - Hjermstad, Marianne

AU - Jakobsen, Gunnhild

AU - Kaasa, Stein

AU - McDonald, James

AU - Ottestad, Inger

AU - Sayers, Judith

AU - Simpson, Melanie

AU - Sousa, Mariana S

AU - Vagnildhaug, Ola Magne

AU - Yule, Michael S

AU - Laird, Barry J A

AU - Skipworth, Richard J E

AU - Solheim, Tora S

AU - Stares, Mark

AU - Arends, Jann

PY - 2025/4/4

Y1 - 2025/4/4

N2 - BackgroundsIn patients receiving anti-cancer treatment, cachexia results in poorer oncologicaloutcomes. However, there is limited understanding and no systematic review ofoncological endpoints in cancer cachexia (CC) trials. This review examines oncologicalendpoints in CC clinical trials.MethodsAn electronic literature search of MEDLINE, Embase and Cochrane databases (1990to 2023) was performed. Eligibility criteria comprised: participants >18 years old;controlled design; >40 participants; and a cachexia intervention for >14 days. Trialsreporting at least one oncological endpoint were selected for analysis. Data extractionwas performed using Covidence and followed PRISMA guidelines and the review wasregistered (PROSPERO CRD42022276710).ResultsFifty-seven trials were eligible, totalling 9,743 patients (median: 107, IQR: 173).Twenty-six (46%) trials focussed on a single tumour site: eight in lung, six inpancreatic, six in head and neck and six in GI cancers. Forty-two (74%) studiesincluded patients with stage III/IV disease and 41 (70%) included patients receivingpalliative anti-cancer treatment. Ten studies (18%) involved patients on curativetreatment. Twenty-eight (49%) studies used pharmacological interventions, 29 (50%)used oral nutrition, and two (4%) used enteral or parenteral nutrition.Reported oncological endpoints included: overall survival (OS, n=46 trials), progressionfree survival (PFS, n=7), duration of response (DR, n=1), response rate (RR, n=9),completion of treatment (TC, n=11) and toxicity/adverse events (AE, n=42). Median OSdiffered widely from 60 to 3,468 days. Of the 50 46 studies, only three reported asignificant positive effect on survival. Seven trials showed a difference in AE, four inTC, one in PFS and one in RR. Reported significances were unreliable due to missingadjustments for extensive multiple testing. Only three of the six trials using OS as theprimary endpoint, reported pre-trial sample size calculations, but only one recruited theplanned number of patients.ConclusionIn CC trials, oncological endpoints were mostly secondary and only few significantfindings have been reported. Due to heterogeneity in oncological settings, nutritionaland metabolic status and interventions, firm conclusions about CC treatment are notpossible. OS and AE are relevant endpoints, but future trials targeting clinicallymeaningul hazard ratios will required more homogeneous patient cohorts, adequatepre-trial power analyses, and adherence to statistical testing standards.

AB - BackgroundsIn patients receiving anti-cancer treatment, cachexia results in poorer oncologicaloutcomes. However, there is limited understanding and no systematic review ofoncological endpoints in cancer cachexia (CC) trials. This review examines oncologicalendpoints in CC clinical trials.MethodsAn electronic literature search of MEDLINE, Embase and Cochrane databases (1990to 2023) was performed. Eligibility criteria comprised: participants >18 years old;controlled design; >40 participants; and a cachexia intervention for >14 days. Trialsreporting at least one oncological endpoint were selected for analysis. Data extractionwas performed using Covidence and followed PRISMA guidelines and the review wasregistered (PROSPERO CRD42022276710).ResultsFifty-seven trials were eligible, totalling 9,743 patients (median: 107, IQR: 173).Twenty-six (46%) trials focussed on a single tumour site: eight in lung, six inpancreatic, six in head and neck and six in GI cancers. Forty-two (74%) studiesincluded patients with stage III/IV disease and 41 (70%) included patients receivingpalliative anti-cancer treatment. Ten studies (18%) involved patients on curativetreatment. Twenty-eight (49%) studies used pharmacological interventions, 29 (50%)used oral nutrition, and two (4%) used enteral or parenteral nutrition.Reported oncological endpoints included: overall survival (OS, n=46 trials), progressionfree survival (PFS, n=7), duration of response (DR, n=1), response rate (RR, n=9),completion of treatment (TC, n=11) and toxicity/adverse events (AE, n=42). Median OSdiffered widely from 60 to 3,468 days. Of the 50 46 studies, only three reported asignificant positive effect on survival. Seven trials showed a difference in AE, four inTC, one in PFS and one in RR. Reported significances were unreliable due to missingadjustments for extensive multiple testing. Only three of the six trials using OS as theprimary endpoint, reported pre-trial sample size calculations, but only one recruited theplanned number of patients.ConclusionIn CC trials, oncological endpoints were mostly secondary and only few significantfindings have been reported. Due to heterogeneity in oncological settings, nutritionaland metabolic status and interventions, firm conclusions about CC treatment are notpossible. OS and AE are relevant endpoints, but future trials targeting clinicallymeaningul hazard ratios will required more homogeneous patient cohorts, adequatepre-trial power analyses, and adherence to statistical testing standards.

U2 - 10.1002/jcsm.13756

DO - 10.1002/jcsm.13756

M3 - Review article

SN - 2190-5991

VL - 16

JO - Journal of Cachexia, Sarcopenia and Muscle

JF - Journal of Cachexia, Sarcopenia and Muscle

IS - 2

M1 - e13756

ER -

Oncological and Survival Endpoints in Cancer Cachexia Clinical Trials: Systematic Review 6 of the Cachexia Endpoints Series

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