Cachexia (disease-related wasting) is a complex metabolic syndrome which occurs in people with chronic illnesses, including cancer, HIV/AIDS, kidney disease, heart disease, and chronic obstructive pulmonary disease (COPD). People with cachexia experience unintentional weight loss, muscle loss, fatigue, loss of appetite, and reduced quality of life.

Multimodal interventions which work synergistically to treat the syndrome could lead to benefits. To assess the benefits and harms of multimodal interventions aimed at alleviating or stabilising cachexia in people with a chronic illness.

We searched CENTRAL, MEDLINE, Embase, PsycINFO, and two trials registers in July 2024, together with reference checking, citation searching, and contact with study authors to identify studies. We included randomised controlled trials (RCTs) in adults with or at risk of cachexia, comparing multimodal interventions combining two or more modalities (of pharmacology, nutrition, exercise) to treatment as usual, variation of the intervention, or unimodal intervention.

Two review authors independently screened potentially eligible studies, extracted data, and assessed risk of bias (RoB 1). Primary outcomes were physical function, strength, and adverse events.

Secondary outcomes were body composition and weight, quality of life (QoL), appetite, fatigue, and biochemical markers. We assessed the certainty of evidence with GRADE.

We included nine studies with 926 adults (mean age: 63 years). Study sample sizes ranged from 20 to 332 participants.

Six studies were conducted in Europe, and one each in Turkey, New Zealand, and the USA. There were six studies in people with cancer, and one each in people with COPD, chronic kidney disease, and HIV/AIDS.

We judged four studies to be at an overall high risk of bias, and five at an overall unclear risk. All outcomes in all comparisons had very low-certainty evidence, downgraded once for risk of bias and/or indirectness and twice for imprecision.

Multimodal intervention (pharmacological, nutritional, and/or exercise) compared to treatment as usual One cancer study randomised 46 participants, with 41 included in all analyses except adverse events. The study assessed outcomes immediately after treatment, lasting six weeks.

Compared to treatment as usual, there is no clear evidence for an effect of a multimodal intervention on: physical function (mean difference (MD) -16.10 m, 95% confidence interval (CI) -79.06 to 46.86; 41 participants); strength (MD 3.80 kg, 95% CI -3.21 to 10.81; 41 participants); adverse events (risk ratio (RR) 1.36, 95% CI 0.70 to 2.65; 46 participants); body composition (MD 7.89 cm, 95% CI -10.43 to 26.21; 41 participants); weight (MD 5.89 kg, 95% CI -1.45 to 13.23; 41 participants); appetite (MD 0.68 points, 95% CI -0.60 to 1.96; 41 participants); fatigue (MD 0.12, 95% CI -1.05 to 1.29; 41 participants); and biochemical markers (MD 2%, 95% CI 0.99 to 3.01; 41 participants), but the evidence was very uncertain; QoL was not reported. Multimodal intervention compared to variation of the intervention Three cancer studies and one HIV/AIDS study randomised 192 participants.

We could not use the available data, nor obtain additional data, from two studies (one in cancer, one in HIV/AIDS). The studies assessed outcomes immediately after treatment, ranging from three to seven months.

Compared to a variation of the intervention, there is no clear evidence for an effect of a multimodal intervention on: physical function (MD 10.0 m, 95% CI -36.27 to 56.27; 1 study, 56 participants); strength (MD 0.7 kg, 95% CI -3.75 to 5.15; 1 study, 56 participants); adverse events (RR 0.87, 95% CI 0.38 to 2.02; P = 0.75, I = 0%; 2 studies, 95 participants); body composition (MD -2.67 kg, 95% CI -5.89 to 0.54; P = 0.10, I = 0%; 2 studies, 95 participants); weight (MD -2.47 kg, 95% CI -7.11 to 2.16; P = 0.30, I = 0%; 2 studies, 95 participants); QoL (standardised mean difference (SMD) -0.15, 95% CI -0.55 to 0.26; P = 0.47, I = 0%; 2 studies, 95 participants); appetite (SMD -0.34, 95% CI -1.27 to 0.59; P = 0.48, I = 79%; 2 studies, 95 participants); fatigue (MD 6.40 points, 95% CI -1.10 to 13.90; 1 study, 56 participants); or biochemical markers (MD 9.80 pg/mL, 95% CI -6.25 to 25.85; P = 0.23, I = 73%; 2 studies, 95 participants), but the evidence is very uncertain. Multimodal intervention compared to unimodal intervention We included six studies (802 participants) in this comparison: three cancer studies, and one each in people with COPD, chronic kidney disease, and HIV/AIDS.

The studies assessed outcomes immediately after treatment, ranging from three to seven months. We could not use the available data, nor obtain additional data, from the HIV/AIDS study.

Compared to a unimodal intervention, there is no clear evidence for an effect of a multimodal intervention on: physical function (SMD 0.02, 95% CI -0.22 to 0.26; P = 0.86, I = 0%; 2 studies, 348 participants); strength (SMD 0.23, 95% CI -0.81 to 1.27; P = 0.66, I = 0%; 2 studies, 348 participants); adverse events (RR 0.87, 95% CI -0.43 to 1.73; P = 0.68, I = 45%; 2 studies, 395 participants); body composition (SMD 0.11, 95% CI -0.28 to 0.50; P = 0.58, I = 74%; 5 studies, 742 participants); body weight (SMD -0.02, 95% CI -0.38 to 0.33; P = 0.90, I = 49%; 4 studies, 431 participants); QoL (SMD 0.22, 95% CI -0.29 to 0.73; P = 0.39, I = 61%; 3 studies, 411 participants); appetite (SMD -0.09, 95% CI -0.58 to 0.40; P = 0.72, I = 58%; 2 studies, 395 participants); fatigue (MD -6.80 points, 95% CI -12.44 to -1.17; 1 study, 244 participants); and biochemical markers (SMD 0.11, 95% CI -0.59 to 0.80; P = 0.76, I = 79%; 3 studies, 411 participants), but the evidence is very uncertain. The review found insufficient evidence to support or refute the use of multimodal interventions in managing cachexia.

The certainty of the evidence was very low. Methodologically rigorous, well-powered RCTs with adequate interaction times are needed to assess the effectiveness of multimodal interventions in managing cachexia across chronic illnesses.