Physical function endpoints in cancer cachexia clinical trials: Systematic Review 1 of the cachexia endpoints series

Abstract

In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function endpoints may be needed alongside other measures. However, it is not clear which physical function endpoints should be used. The aim of this systematic review was to assess the frequency and diversity of physical function endpoints in cancer cachexia trials. Following a comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990–2021), records were retrieved. Eligible trials met the following criteria: adults (≥18 years), controlled design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a physical function endpoint. Physical function measures were classified as an objective measure (hand grip strength [HGS], stair climb power [SCP], timed up and go [TUG] test, 6‐min walking test [6MWT] and short physical performance battery [SPPB]), clinician assessment of function (Karnofsky Performance Status [KPS] or Eastern Cooperative Oncology Group‐Performance Status [ECOG‐PS]) or patient‐reported outcomes (physical function subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaires [EORTC QLQ‐C30 or C15]). Data extraction was performed using Covidence and followed PRISMA guidance (PROSPERO registration: CRD42022276710). A total of 5975 potential studies were examined and 71 were eligible. Pharmacological interventions were assessed in 38 trials (54%). Of these, 11 (29%, n = 1184) examined megestrol and 5 (13%, n = 1928) examined anamorelin; nutritional interventions were assessed in 21 trials (30%); and exercise‐based interventions were assessed in 6 trials (8%). The remaining six trials (8%) assessed multimodal interventions. Among the objective measures of physical function (assessed as primary or secondary endpoints), HGS was most commonly examined (33 trials, n = 5081) and demonstrated a statistically significant finding in 12 (36%) trials (n = 2091). The 6MWT was assessed in 12 trials (n = 1074) and was statistically significant in 4 (33%) trials (n = 403), whereas SCP, TUG and SPPB were each assessed in 3 trials. KPS was more commonly assessed than the newer ECOG‐PS (16 vs. 9 trials), and patient‐reported EORTC QLQ‐C30 physical function was reported in 25 trials. HGS is the most commonly used physical function endpoint in cancer cachexia clinical trials. However, heterogeneity in study design, populations, intervention and endpoint selection make it difficult to comment on the optimal endpoint and how to measure this. We offer several recommendations/considerations to improve the design of future clinical trials in cancer cachexia.

Relevance of Cardiovascular Exercise in Cancer and Cancer Therapy-Related Cardiac Dysfunction

“…Resistance training (RT), as a measure to reduce or even reverse muscle wasting, is recommended in addition to endurance training to improve CRF by current guidelines of sports cardiology and cardio-oncology [ 8 , 94 ] as it improves skeletal muscle and mitochondrial respiration [ 95 ]. Assessment of muscle strength in cancer patients is usually performed by measuring handgrip strength [ 96 ], and RT intensity to establish training prescriptions should be identified by the one repetition maximum (1 RPM) [ 89 , 94 ]. A meta-analysis of randomized trials of RT during and after chemotherapy in cancer survivors demonstrated the most effective increase of muscle strength at intensities below 75% of 1 RPM [ 97 ] and provides evidence for a safe integration of RT into training of cancer patients.…”

“…Recent trials used combined AET and RT to demonstrate improvement of CRF in patients during and after chemotherapy [ 50 •, 65 •, 98 ], but did not include frail and sarcopenic patients [ 96 , 99 ]. Future exercise studies in cancer patients need to take this into account and should also enroll sarcopenic cancer patients who should be trained with combined RT and AET and additional structured nutritional advice.…”

La cachexie associée au cancer

“…Des progrès dans ces domaines permettraient à la fois d'intervenir à des stades de pré-cachexie, où les symptômes pourraient être encore réversibles, et de personnaliser l'approche thérapeutique de cette maladie très hétérogène. L'amélioration du diagnostic permettrait aussi de mieux définir les critères d'efficacité proposés dans les protocoles d'essais cliniques, souvent remis en question par les agences réglementaires [27] . Il est désormais admis que la prise en charge de la cachexie devrait être multimodale, associant, en combinaison, des thérapies ciblées anaboliques, anticataboliques et anti-inflammatoires, des approches nutritionnelles et pharmacologiques de l'anorexie, et des protocoles d'exercice physique visant à contenir la perte musculaire [28].…”

A Review of Olanzapine in the Treatment of Cancer Anorexia-Cachexia Syndrome

“…CAS is a complex multifactorial syndrome with ongoing skeletal muscle loss despite nutritional intervention, and the patient may or may not present with fat mass loss [3]. It is a significant clinical finding of great importance because the presence of cachexia is associated with shorter survival [4][5][6], poor physical functioning [7], reduced response to chemotherapy, and a negative impact on the quality of life [8]. Refractory cachexia in advanced non-curable cancer patients has a prognosis of less than 3 months [9].…”