Madeddu, C., Dessi, M., Panzone, F., Serpe, R., Antoni, G., Cau, M.C., . . . Mantovani, G. (2011). Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib +/- megestrol acetate for patients with cancer-related anorexia/cachexia syndrome. Clinical Nutrition, 31, 176–182.

To compare the efficacy and safety of a two-drug combination (including nutraceuticals) with carnitine and celecoxib (arm 1) versus megestrol acetate (arm 2) for the treatment of cancer anorexia and cachexia syndrome

No dietary restrictions were placed on participants. Polyphenols (2 tabs, 300 mg/day), lipoic acid (300 mg/day), carbocystine (400 mg/day), vitamin A (30,000 IU/day), and vitamin C (500 mg/day) were administered orally to all patients. Patients were then randomized to treatment arms: arm 1, L-carnitine (4 g/day) + celecoxib, or arm 2, l-carnitine (4 g/day) + celecoxib + megestrol acetate (MA) (320 mg/day). Treatment duration was four months. Measurements were obtained at 4, 8, and 16 weeks. Analysis focused on differences from baseline to 16 weeks. Data were collected from 2009 to 2010. No placebo arm was included for ethical reasons and based on previous research. Planned study duration was four months.

• The study reported on 60 patients.
• Mean patient age was 65.2 years (SD = 8.7), with a range of 46–82 years.
• The sample was 58.6% male and 41.4% female.
• Most patients (96.6%) had stage IV disease, and one patient was stage IIIB.
• Patients had a variety of diagnoses, including head and neck, lung, colorectal, stomach, ovarian, and pancreatic cancers. One patient had esophageal cancer.
• Seventy-six percent of patients were receiving concomitant palliative chemotherapy.

• Single site
• Setting not specified
• Medical oncology, Cagliari, Italy

• Patients were undergoing long-term follow-up care.
• The study has clinical applicability for end-of-life and palliative care, and late effects and survivorship.

A phase III, randomized, two-group, non-inferiority trial design was used.

• Lean body mass (LBM): bioelectrical impedance analysis (BIA), dual-energy x-ray absorptiometry (DEXA), and regional computed tomography (CT) at L3    
• Total daily physical activity and resting energy expenditure (REE): electronic armband
• Secondary endpoints: grip strength, six-minute walking test, fatigue, REE < body weight, appetite (measured by visual analog scale), interleukin 6 (IL-6), c-reactive protein (CRP), tumor necrosis factor (serum blood marker), and quality of life (European Organization for Research and Treatment Cancer Core Quality of Life questionnaire [EORTC QLQ-C30])
• Safety: adverse events classified by the National Cancer Institute Common Terminology Criteria for Adverse Events
• Multidimensional Fatigue Symptom Inventory–Short Form

Primary endpoints: There was no significant difference (based on t test) between arms for LBM and physical activity. DEXA and CT of L3 significantly increased at 16 weeks from baseline in both arms. BIA did not change in either arm. There were no significant changes in physical activity in either arm. The six-minute walking test improved in both arms, and grip strength did not change significantly in either arm. REE, fatigue, Eastern Cooperative Oncology Group score, and prognostic score decreased significantly in both arms. Body weight did not change significantly in arm 1 but did increase in arm 2 (p = 0.052, which was not significant but on the border and trending). Appetite was reported as improved significantly in both arms (p < 0.05). Fatigue scores were improved significantly in arm 1 after treatment  (p = 0.036). Survival measurements did not change and were not significantly different between groups. Two patients reported grade 3 diarrhea.

No significant differences were found in patients based on the intervention arm.

• The study had a small sample size, with less than 100 patients.
• Adherence to treatment, patient-reported outcomes, and impact of each individual drug were not reported. Therefore, it was difficult to know which medication had the impact.
• This was a small, single-site study. Although significant improvements in appetite were reported, there is no description of how this was measured.
• The report states a planned follow-up of four months but does not state how long the follow-up actually was.

A multimodal approach may help to improve anorexia and cachexia in patients with cancer. More work focused on patient-reported outcomes, safety, and adherence is needed. Specific description of how appetite is assessed should be included in studies reporting this outcome measure.