Maccio, A., Madeddu, C., Gramignano, G., Mulas, C., Floris, C., Sanna, E., . . . Mantovani, G. (2012). A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: Evaluating the impact on metabolic and inflammatory profiles and quality of life. Gynecologic Oncology, 124, 417–425.

To compare the efficacy and safety of (arm 1) combined treatment with L-carnitine (4 g/day) plus celecoxib (300 mg/day) plus antioxidants (lipoic acid 600 mg/day, carbocysteine 2.7 g/day) plus megestrol acetate (MA) 320 mg/day versus (arm 2) MA 320 mg/day alone (considered standard of care) for the treatment of advanced neoplastic disease-associated symptoms in gynecologic patients with progressive or recurrent disease previously treated with one or more lines of chemotherapy

Primary endpoints included increase in lean body mass (LBM), decrease in resting energy expenditure (REE), decrease in fatigue, and an improvement in global quality of life (QOL). Secondary endpoints included appetite, grip strength, Glasgow Prognostic Score (GPS), Eastern Cooperative Oncology Group (ECOG) performance score, and serum markers of inflammation and oxidative stress: C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor (TNF), leptin, reactive oxygen species (ROS), glutathione peroxidase (GPx), and superoxide dismutase (SOD). 

Baseline anthropometric measures, physical examination, vital signs, tumor site, stage, chemotherapy regimen, weight loss in previous three to six months, performance status, Glasgow Prognostic Score, and QOL were assessed. After baseline assessment, randomization was completed by a biostatistician to arm 1 or arm 2. Treatment duration was planned for four months. All patients received 150 UI/kg of low molecular weight heparin subcutaneously for the treatment duration. Endpoints were assessed at baseline (before treatment) and at 4, 8, and 16 weeks, although all analysis was presented as a comparison between baseline and 16 weeks. Safety was monitored with weekly evaluations of adverse events and toxicity. All patients also received psychosocial counseling.

• The study reported on 124 patients.
• Mean patient age was 60.5 years (SD = 12.74), with a range of 35–76 years.
• The sample was 100% female.
• Patients had histologically confirmed advanced-stage gynecologic tumors with progressive or recurrent disease after one or more lines of chemotherapy, loss of at least 5% of ideal or preillness body weight in the previous three months, and life expectancy of more than six months. Patients could be treated with concomitant antineoplastic chemotherapy with palliative intent (low-dose regimens). All had cancer of the endometrium, cervix, or ovary (mostly stage IV, with five patients having stage IIIC).
• Patients with mechanical obstruction, history of thromboembolism, cardiac disease, cerebrovascular events, inflammatory bowel disease, or gastrointestinal ulcers were excluded.

This multisite study was conducted in an inpatient setting in 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.

This was an open-label, randomized, controlled, prospective study.

• LBM: dual-energy x-ray absorptiometry assessment    
• REE: indirect calorimetry  
• Fatigue: Multidimensional Fatigue Symptom Inventory–short form
• QOL: European Organization for Research and Cancer Core Quality of Life questionnaire (EORTC QLQ-C30, Italian version)
• Secondary endpoints: Grip strength: dynamometer; appetite: visual analog scale, performance status (ECOG scale), GPS, and serum markers for inflammation and oxidative stress: IL-6, TNF, CRP, leptin, ROS, GPx, and SOD

Groups were similar in patient characteristics. At 16 weeks, LBM increased significantly (p = 0.032) in arm 1 with a mean difference of +4.65 kg compared to arm 2. REE changes were decreased significantly in arm 1 (p = 0.046) compared to arm 2. Arm 1 had significant decreases in fatigue symptoms (p = 0.049) and a higher mean QOL score (p = 0.042) compared to arm 2. Arm 1 gained a significant amount of weight with a mean increase of 0.5 kg per week over 16 weeks (p = 0.002). REE and fatigue decreased in arm 1 significantly at 16 weeks but not in arm 2. Both arms had significantly increased appetite (p < 0.05) and decreased ECOG scores. There was no difference between groups in appetite. Serum markers for inflammation and oxidative stress decreased significantly in arm 1 at 16 weeks. No significant arm 2 findings resulted. Leptin increased significantly in arm 1 and moderately but nonsignificantly in arm 2. Two patients had grade 3 diarrhea in arm 1.

The multimodal arm (arm 1) had improved physical, inflammatory, oxidative stress markers and QOL compared to MA alone, but did not appear to make a difference in appetite.

• There are challenges to clinical application due to the complexity of symptoms and clinical management; which component of the multimodal arm 1 intervention had the effect is unclear.
• The sample included patients with gynecologic cancers only.
• Safety and toxicity were described and measured minimally. 
• Although the study reports significant improvements in fatigue and anorexia, there is no description of how these were measured.

Study findings support multimodal approaches, including psychosocial support, for symptom management. More work should include patient-reported outcomes, toxicity, and safety of the intervention.