Power Comparisons and Clinical Meaning of Outcome Measures in Assessing Treatment Effect in Cancer Cachexia: Secondary Analysis From a Randomized Pilot Multimodal Intervention Trial

Abstract

Background: New clinical trials in cancer cachexia are essential, and outcome measures with high responsiveness to detect meaningful changes are crucial. This secondary analysis from a multimodal intervention trial estimates sensitivity to change and between treatment effect sizes (ESs) of outcome measures associated with body composition, physical function, metabolism, and trial intervention.Methods: The study was a multicenter, open-label, randomized pilot study investigating the feasibility of a 6-week multimodal intervention [exercise, non-steroidal anti-inflammatory drugs, and oral nutritional supplements containing polyunsaturated fatty acids (n−3 PUFAs)] vs. standard cancer care in non-operable non-small-cell lung cancer and advanced pancreatic cancer. Body composition measures from computerized tomography scans and circulating biomarkers were analyzed.Results: Forty-six patients were randomized, and the analysis included 22 and 18 patients in the treatment and control groups, respectively. The between-group ESs were high for body weight (ES = 1.2, p < 0.001), small for body composition and physical function [handgrip strength (HGS)] measures (ES < 0.25), moderate to high for n-3 PUFAs and 25-hydroxyvitamin D (25-OH vitamin D) (ES range 0.64–1.37, p < 0.05 for all), and moderate for serum C-reactive protein (ES = 0.53, p = 0.12). Analysis within the multimodal treatment group showed high sensitivity to change for adiponectin (ES = 0.86, p = 0.001) and n-3 PUFAs (ES > 0.8, p < 0.05 for all) and moderate for 25-OH vitamin D (ES = 0.49, p = 0.03). In the control group, a moderate sensitivity to change for body weight (ES = −0.84, p = 0.002) and muscle mass (ES = −0.67, p = 0.016) and a high sensitivity to change for plasma levels of 25-OH vitamin D (ES = −0.88, p = 0.002) were found.Conclusion: Demonstrating high sensitivity to change and between treatment ES and body composition measures, body weight still stands out as a clinical and relevant outcome measure in cancer cachexia. Body composition and physical function measures clearly are important to address but demand large sample sizes to detect treatment group differences.Trial registration:ClinicalTrials.gov identifier: NCT01419145.

The Effect of Exercise and Nutritional Interventions on Body Composition in Patients with Advanced or Metastatic Cancer: A Systematic Review

“…Of the twenty studies included in this systematic review, sixteen (80%) describe original results from randomized-controlled trials (RCTs) [ 48 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ], three (15%) from non-randomized controlled trials [ 82 , 83 , 84 ], and one (5%) was a secondary analysis [ 85 ] of another [ 71 ]. The articles included within this analysis were published between 2013 and 2022 and conducted across the globe including Denmark ( n = 4) [ 67 , 74 , 78 , 79 ], Germany ( n = 3) [ 75 , 83 , 84 ], the United Kingdom ( n = 3) [ 71 , 81 , 85 ], Australia ( n = 3) [ 48 , 69 , 73 ], the United States ( n = 2) [ 80 , 82 ], Switzerland ( n = 2) [ 68 , 77 ], Norway ( n = 2) [ 71 , 85 ], Taiwan ( n = 1) [ 70 ], India ( n = 1) [ 72 ], and the Netherlands ( n = 1) [ 76 ].…”

“…In total, 1091 patients were allocated to the interventions of the included studies with an average age ranging from 44.0 [ 72 ] to 76.9 years old [ 48 ] and where six studies (30%) exclusively examined males [ 48 , 67 , 69 , 73 , 74 , 78 ] and two studies (10%) examined females [ 72 , 80 ]. Twelve studies (60%) exclusively targeted specific cancer types or anatomical regions, which included six (30%) examining prostate cancer [ 48 , 67 , 69 , 73 , 74 , 78 ], one (5%) examining breast cancer [ 80 ], four (20%) including patients with gastrointestinal cancers [ 70 , 75 , 76 , 81 ], and one (5%) including patients with head and neck cancers [ 82 ], whilst the remaining eight (40%) included mixed populations [ 68 , 71 , 72 , 77 , 79 , 83 , 84 , 85 ]. The cancer stages reported within the studies include six (30%) exclusively involving patients with metastatic cancer [ 48 , 69 , 73 , 76 , 78 , 80 ] and six (30%) examining a mixture of locally advanced, advanced, and metastatic patients [ 67 , 68 , 74 , 77 , 79 , 81 ], whilst six (30%) reported the inclusion of patients with stage III and IV cancer […”

“…Twelve studies (60%) exclusively targeted specific cancer types or anatomical regions, which included six (30%) examining prostate cancer [ 48 , 67 , 69 , 73 , 74 , 78 ], one (5%) examining breast cancer [ 80 ], four (20%) including patients with gastrointestinal cancers [ 70 , 75 , 76 , 81 ], and one (5%) including patients with head and neck cancers [ 82 ], whilst the remaining eight (40%) included mixed populations [ 68 , 71 , 72 , 77 , 79 , 83 , 84 , 85 ]. The cancer stages reported within the studies include six (30%) exclusively involving patients with metastatic cancer [ 48 , 69 , 73 , 76 , 78 , 80 ] and six (30%) examining a mixture of locally advanced, advanced, and metastatic patients [ 67 , 68 , 74 , 77 , 79 , 81 ], whilst six (30%) reported the inclusion of patients with stage III and IV cancer [ 71 , 75 , 82 , 83 , 84 , 85 ], and the remaining two studies (10%) reported the inclusion of advanced [ 72 ] or locally advanced patients [ 70 ].…”

“…During the respective study intervention periods, 12 studies (60%) examined patients who were actively receiving or about to receive treatment as dictated as part of their inclusion criteria. These treatments included chemotherapy ( n = 6; 30%) [ 71 , 75 , 76 , 81 , 82 , 85 ], chemoradiotherapy ( n = 1; 5%) [ 70 ], and androgen deprivation therapy ( n = 2; 10%) [ 67 , 74 ], with three (15%) studies examining patients on a range of treatments (e.g., chemotherapy, immunotherapy, targeted therapy, radiotherapy, hormone therapy) [ 79 , 83 , 84 ]. Of the remaining studies, five (25%) reported some patients to be receiving treatment (e.g., anti-androgen monotherapy, castration, chemotherapy, endocrine therapy, immunotherapy) but treatment status was not an inclusion criterion [ 48 , 73 , 77 , 78 , 80 ], two (10%) did not report any active treatment [ 68 , 69 ], and one (5%) reported patients to be receiving palliative care but did not specify treatment regimens [ 72 ].…”

Cancer Cachexia: Its Mechanism and Clinical Significance

“…A multidisciplinary intervention model for cancer cachexia is presented in Figure 3. In addition to anti-inflammatory, metabolism-improving, and appetite-improving medications, high-quality nutritional therapy and appropriate exercise tailored to the patient's physical function can help improve physical function as well as increase skeletal muscle mass [112][113][114]. These strategies will become even more necessary in the future.…”