Wilkes, E.A., Selby, A.L., Cole, A.T., Freeman, J.G., Rennie, M.J., & Khan, Z.H. (2011). Poor tolerability of thalidomide in end-stage oesophageal cancer. European Journal of Cancer Care, 20, 593–600.

To test the hypothesis that thalidomide is superior to placebo in terms of weight gain in patients with cachexia caused by esophageal cancer

Patients with advanced esophageal cancer who were not in active disease treatment were recruited at multidisciplinary team meetings at an individual site and randomly assigned to receive either placebo or 200 mg of thalidomide daily. Total body weight, lean body mass, resting energy expenditure measurements, and blood samples (complete blood count, biochemistry, tumor necrosis factor [TNF]-alpha, and interleukin 1-beta)  were taken at baseline and after six weeks of therapy. At two and four weeks, triceps skinfold thickness, mid-arm circumference, disease progression symptoms, adverse drug reactions, Karnofsky Performance Status score, and Piper Fatigue Scale questionnaire data were collected.

• The study reported on 22 patients.
• Mean patient age was 68 years, with a range of 57.7–80.2 years.
• The sample was 82% male and 18% female.
• Patients were diagnosed with incurable advanced esophageal cancer.
• Patients were excluded if they were in active treatment (surgery, chemotherapy, or radiation) but were eligible if treatment had taken place no less than four weeks prior.

The study site was not stated, but it appears to be a single site in an outpatient setting located in the United Kingdom.

• Patients were undergoing the end-of-life phase of care.
• The study has clinical applicability for end-of-life care.

A randomized, placebo-controlled trial design was used.

• Calibrated electronic scales to measure total body weight
• Dual-energy x-ray absorptiometry to measure lean body mass
• Triceps skinfold thickness
• Mid-arm circumference
• Karnofsky Performance Status index (performance indices)
• Piper Fatigue Scale Questionnaire    
• Blood: complete blood count, chemistries, TNF-alpha, and interleukin 1-beta
• Disease progression symptoms
• Adverse drug reaction information
• Indirect calorimetry via a vented hood apparatus to measure resting energy expenditure

At the end of the six-week study period, neither lean body mass nor total body weight changed from baseline in the treatment or in the placebo group. Mid-arm muscle circumference did not show changes at two or four weeks. None of the body composition endpoints showed any significant difference between groups (p > 0.05). The placebo group had a statistically significant increase in resting energy expenditure (p = 0.04), which was not shared with the treatment group.  

Survival was not different between the two groups. The median Karnofsky performance score was 10 points higher at baseline for the placebo group and did not change during the study, but this was not significant. The treatment group's median Karnofsky score dropped by 10 points. The Piper fatigue score did not change in either group.

TNF-alpha scores remained the same for both groups pre- and post-treatment. The interleukin 1-beta scores increased in the placebo arm.

Patients with advanced esophageal cancer taking thalidomide to increase body weight or lean muscle mass did not benefit positively from the intervention. There were many treatment arm drop-outs, mostly due to drug toxicity. All but two study arm patients who were able to complete the study required a dose reduction of thalidomide. Forty-seven percent of treatment patients were unable to complete the six-week study, whereas 94% of the placebo arm patients did complete it.

• The study had a small sample size and was conducted in a group of patients with a high rate of mortality and morbidity. The study was powered for 17 patients in each arm to be clinically significant, and this number was not met.
• Treatment patients had a lower Karnofsky performance score at baseline compared to placebo patients.
• Preliminary data from a pilot study used to design this study were gathered from patients with esophageal cancer who had not yet received treatment, suggesting an earlier intervention in their disease course and giving more favorable data to the intervention.
• The burden of treatment was so high that it interfered with data collection.

In this small study, the benefit of thalidomide for patients with advanced esophageal cancer was eclipsed by the drug’s adverse reactions and side effects. Quality of life was not enhanced and was actually negatively impacted. Although patients with advanced disease are often concerned about anorexia and weight loss, this study did not demonstrate benefit to the introduction of thalidomide in the end stages of life for patients with esophageal cancer.