Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia

Abstract

Purpose: A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia-lean body mass (LBM), resting energy expenditure (REE), and fatigue-and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines.

Patients and methods: Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months.

Results: Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms.

Conclusion: The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents.

Figure 1.

Consort diagram. Abbreviation: PD, progressive disease.

Figure 2.

Assessment of total daily physical activity and the associated energy expenditure. Total energy expenditure (TEE) (A) as well as active energy expenditure (AEE) (B) increased significantly in arm 5. Bars in (A) show TEE calculated as kcal/24-hour consumption. Bars in (B) show AEE expressed as the number of kcal/24 hours consumed beyond the limit of 3.0 metabolic equivalents (METs) and the number of minutes of activity >3.0 METs. 1 MET equals oxygen consumption of 3.5 ml O₂/kg per minute or 1 kcal/kg per hour, both equal to resting energy expenditure.