Mantovani, G., Maccio, A., Madeddu, C., Serpe, R., Massa, E., Dessi, M., . . . Contu, P. (2010). Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. Oncologist, 15, 200–211.

To determine the most effective and safest treatment to improve primary endpoints of lean body mass, resting energy expenditure, and fatigue in patients with cancer-related anorexia-cachexia syndrome

To determine the effects on secondary endpoints of appetite, quality of life, grip strength, Glasgow Prognostic Score, and proinflammatory cytokines

All patients were given the following standard treatment orally via pills or dietary intake:

• 300 mg/day polyphenols
• 300 mg/day lipoic acid
• 2.7g/day carbocysteine
• 400 mg/day vitamin E
• 30,000 IU/day vitamin A
• 500 mg/day vitamin C

Patients were randomly assigned to one of the following five treatment arms:

1. 500 mg/day medroxyprogesterone acetate (MPA) or 320 mg/day megestrol acetate (MA) (considered equivalent)
2. An eicosapentaenoic acid (EPA)-enriched nutritional supplement (2 cartons/day for 2.2 g EPA)
3. 4 g/day L-carnitine
4. 200 mg/day thalidomide
5. Combination of all of the above treatments

Planned treatment duration was four months.

• The study reported on 332 patients. 
• Mean age across all study groups ranged from 60.6 to 62.8 years. There were no differences between groups. All patients were older than 18 years of age.
• The sample was 55% male and 45% female.
• Patients were diagnosed with any type of cancer and experienced loss of more than 5% of their ideal or preillness body weight in the previous three months.
• All patients had stage III or IV disease; 50% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and 50% had a performance status of 2–3; and 78% were receiving concomitant palliative chemotherapy.

The multisite study was conducted in Italy.

The study was a phase III, prospective, randomized trial.

• Lean body mass (LBM) was assessed by bioelectrical impedance in all patients and by dual-energy x-ray absorptiometry (DEXA) and regional computed tomography (CT) in some patients.
• Resting energy expenditure (REE) was assessed by indirect calorimetry.
• Fatigue was assessed with the Multidimensional Fatigue Symptom Inventory–short form.
• Appetite was assessed via a visual analog scale (VAS).
• Quality of life (QOL) was assessed via the European Oncology Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30).
• Multiple cytokines (interleukin, tumor necrosis factor) were evaluated.
• Total energy expenditure was calculated as REE plus measured activity expenditure from an electronic armband device.
• ECOG performance status was reported.

• Twelve patients withdrew due to disease progression. The drop-out rate was not significantly different between study arms.
• LBM measured by DEXA (p = 0.015) and CT (p = 0.001) increased in arm 5.
• REE decreased significantly in arm 5 (p = 0.047).
• Appetite increased significantly in arm 5 (p = 0.003).
• Fatigue decreased significantly in arm 5 (p = 0.047).
• ANOVA and post hoc analysis showed a significant difference in REE (p = 0.028) and fatigue (p = 0.035) findings in arm 5 compared to other groups.
• There was a trend toward increased grip strength in arms 3, 4, and 5.
• ECOG performance status increased significantly in arms 3, 4, and 5 (p </= 0.0001), ranging from a 0.2 to 0.05 average score reduction.
• There were no significant changes in overall QOL measurement.
• Arms 4 and 5 showed reduction in cytokines measured.
• Two patients with grade 3 or 4 diarrhea were reported in arms 3 and 5. Toxicity was comparable among treatment arms and was negligible.

Results demonstrate efficacy of a combined treatment approach in cancer cachexia syndrome.

Results seem to confirm that cancer cachexia, as a multidimensional syndrome, is likely to yield success with a multifactorial approach.

Results appear to confirm thinking that cachexia is driven by inflammatory cytokines and that drugs that down-regulate the production and/or release of proinflammatory cytokines can be effective in reversing the symptoms of the syndrome.

It is noted that the drugs and dietary supplements used are low cost.

• Results may not be readily generalizeable for broad clinical application since the treatment may appear difficult, particularly in cachectic patients who often have an already huge drug burden.
• This study was done in patients with advanced disease and a documented cachexia syndrome. Findings may not be applicable to other patient groups for management of appetite and fatigue.

Combined treatments used here may indicate an additive or synergistic effect of the agents.