Thalidomide

Thalidomide

PEP Topic 
Anorexia
Description 

Thalidomide was used in the 1960s as an anxiolytic and antiemetic agent for pregnant women and was withdrawn from use because of its teratogenic effects. Because of its anti-angiogenic properties, it has resurfaced as an antineoplastic drug and currently is indicated for the treatment of multiple myeloma. Thalidomide reduces the production of tumor necrosis factor alpha. It has been used in AIDS-associated cachexia and has been studied in cancer-related anorexia/cachexia. Adverse effects include dizziness, drowsiness, somnolence, constipation, and increased incidence of thromboembolic events. The use of thalidomide is strictly regulated due to its teratogenic effects. Thalidomide use has been examined in patients with cancer for anorexia, fatigue, and chemotherapy-induced nausea and vomiting.

Effectiveness Not Established

Research Evidence Summaries

Bruera, E., Neumann, C.M., Pituskin, E., Calder, K., Ball, G., & Hanson, J. (1999). Thalidomide in patients with cachexia due to terminal cancer: Preliminary report. Annals of Oncology, 10, 857–859.

doi: 10.1023/A:1008329821941
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Intervention Characteristics/Basic Study Process:

Patients received 100 mg of thalidomide by mouth at night for 10 days. If improvement was shown, patients could continue.

Sample Characteristics:

  • A total of 72 patients entered the study; 37 were evaluable.
  • Patients were eligible for study if they
    • Had metastatic cancer
    • Were not receiving antineoplastic therapy
    • Experienced weight loss of more than 5% of usual weight
    • Had a life expectancy of more than two weeks
    • Had normal cognition
    • Were postmenopausal or had no possibility of becoming pregnant; men could not have sexual activity with women who could become pregnant.

Study Design:

This was an open-label study.

Measurement Instruments/Methods:

  • Visual analog scale measuring
    • Difficulty falling asleep
    • Morning restedness
    • Insomnia
    • Nausea
    • Appetite
    • Sensation of well-being
  • Caloric intake form

Results:

More than 30% improvement in symptom intensity was observed in the following parameters: difficulty falling asleep (17/35 = 49%), morning restedness (23/36 = 64%), insomnia (22/32 = 69%), nausea (16/36 = 44%), appetite (22/35 = 63%), and well-being (18/34 = 53%). Twenty-seven patients completed food intake forms on days 1 and 10. Caloric intake increased from 1,325 to 1,531 calories per day (p = 0.047). Three patients discontinued thalidomide because of adverse effects: dizziness (1) and drowsiness (2).

Limitations:

  • The study had a high attrition rate and poor compliance, possibly because of survival expectations of only more than 2 weeks.
  • The study was open and subject to bias.

Nursing Implications:

Findings need to be confirmed in double-blind studies.

Davis, M., Lasheen, W., Walsh, D., Mahmoud, F., Bicanovsky, L., & Lagman, R. (2012). A phase II dose titration study of thalidomide for cancer-associated anorexia. Journal of Pain and Symptom Management, 43, 78–86.

doi: 10.1016/j.jpainsymman.2011.03.007
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Study Purpose:

To assess appetite response to thalidomide in cancer-associated anorexia

Intervention Characteristics/Basic Study Process:

Patients with advanced cancer were given 50 mg of thalidomide at bedtime for two weeks. Those who responded to treatment were kept on the same dose for a total of six weeks. Those who did not respond to the 50 mg dose and were not experiencing dose-limiting toxicity were given 100 mg at night for two more weeks. If there was no response at 100 mg after two weeks and the patient was not having dose-limiting toxicity, the dose was escalated to 200 mg at bedtime.

Sample Characteristics:

  • The study reported on a sample of 33 patients.  
  • Median patient age was 69 years, with a range of 43–87 years.
  • The sample was 51% male and 49% female.
  • Patients had advanced, active cancer.

 

Setting:

  • Single site
  • Outpatient setting
  • United States

Phase of Care and Clinical Applications:

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

Study Design:

A prospective, observational study design was used.

Measurement Instruments/Methods:

  • Medical history
  • Neurologic exam
  • Appetite, strength, pain, insomnia, night sweats, and nausea measured by 0–10 numerical rating scale (NRS)
  • Appetite, tiredness, early satiety, quality of life, and toxicities (muscle cramps, pain, confusion, constipation, dizziness, drowsiness, dry mouth, headache, loss of interest in sex, nervousness, stomach pain, dry skin or pruritius, and limb swelling) measured by categorical scale (patient-perceived severity by a categorical scale [CAT])
  • Eastern Cooperative Oncology Group–PS (performance score)
  • Weight
  • C-reactive protein (CRP)
  • Lean body mass by Bioelectric Impedance (BIA)

Results:

Thirty-three patients completed at least 14 days of therapy. Sixty-four percent of patients who had completed at least two weeks of thalidomide had statistically significant appetite improvement by both the NRS and CAT (p < 0.001). Other symptoms with statistically significant improved scores included pain (< 0.05), insomnia (night sleep) (< 0.01), and early satiety (< 0.05).

Conclusions:

Thalidomide significantly improved appetite, insomnia, pain, and early satiety from baseline in patients with advanced cancer.

Limitations:

  • The study count is not clear as to how long patients were on which dose of thalidomide. Thirty-three patients received 50 mg for 14 days. At that time, 17 had improved appetite and 9 of the 16 nonresponders were titrated up to 100 mg. At this point it is not clear what happened with the other seven patients, but the study goes on to say that seven withdrew after two weeks, suggesting that the seven who dropped out received the 100 mg dose, which the manuscript does not corroborate. Although the methods stated that patients were titrated up to 200 mg, the results do not mention this.  
  • The study states that side effects were "negligible," yet at least 5 of 33 patients dropped out of the study due to side effects.  
  • There was no control group for this study. Some of the lack of response to the study drug could have been due to disease progression or performance status deterioration. A larger study with a control group may have provided comparison data to assess this point.
  • Adherence to medication administration was not measured.

Nursing Implications:

Thalidomide may provide benefit for appetite stimulation as well as some other symptoms of advanced disease; however, the drug is not without side effects that may interfere with quality of life. This was a small study, partially funded by a pharmaceutical company, so the results should be interpreted with caution. Patients with advanced cancers on thalidomide should be educated about and assessed frequently for toxicities that may erode what little quality of life they have. Nurses must advocate for their patients who are experiencing unacceptable toxicities.

Gordon, J.N., Trebble, T.M., Ellis, R.D., Duncan, H.D., Johns, T., & Goggin, P.M. (2005). Thalidomide in the treatment of cancer cachexia: A randomised placebo controlled trial. Gut, 54, 540–545.

doi: http://dx.doi.org/10.1136/gut.2004.047563
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Study Purpose:

To evaluate the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia secondary to advanced pancreatic cancer

Intervention Characteristics/Basic Study Process:

Fifty patients were randomized to receive 200 mg of thalidomide by mouth daily or placebo for 24 weeks. At four weeks, 33 patients were evaluated; at eight weeks, 20 patients were evaluated.

Sample Characteristics:

Patients were included in the study if they

  • Had inoperable pancreatic cancer
  • Experienced 10% weight loss over the preceding six months
  • Had a life expectancy of at least six weeks.

Patients were excluded if they

  • Had received any form of antineoplastic treatment in the preceding six weeks
  • Weighed less than 40 kg
  • Concurrently used steroids, anabolic drugs, hormonal agents, or appetite stimulants
  • Were younger than 18 years of age
  • Had peripheral neuropathy
  • Had severe constipation.

Study Design:

The study was a randomized, placebo-controlled trial.

Measurement Instruments/Methods:

  • Primary outcome: Change in weight at four weeks
  • Secondary outcomes:
    • Change in bone and free muscle mass
    • Grip strength
    • Quality of life (physical performance and global health status)
    • Survival

Results:

At four weeks, 33 patients were evaluable. The thalidomide arm gained 0.37 kg in weight and 1 cm3 of arm circumference muscle mass. The placebo arm lost 2.21 kg in weight and 4.46 cm3 of arm circumference muscle mass.

At eight weeks, 20 patients were evaluable. The thalidomide arm lost 0.06 kg in weight and 0.5 cm3 of arm circumference muscle mass. The placebo arm lost 3.62 kg in weight and 8.4 cm3 of arm circumference muscle mass.

Conclusions:

Thalidomide was well tolerated and effective at attenuating weight loss and loss of lean body mass. Findings were unable to demonstrate that attenuation in weight loss led to improvement in quality of life.

Limitations:

  • The study had a high attrition rate: 70% were evaluable at four weeks, and 43% were evaluable at eight weeks.
  • Baseline weight in the control group was 4 kg lighter.
  • Change in appetite was not measured as a primary outcome.

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.

doi: 10.1634/theoncologist.2009-0153
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Study Purpose:

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

Intervention Characteristics/Basic Study Process:

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.

Sample Characteristics:

  • 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.

Setting:

The multisite study was conducted in Italy.

Study Design:

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

Measurement Instruments/Methods:

  • 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.

Results:

  • 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.

Conclusions:

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.

Limitations:

  • 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.

Nursing Implications:

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

Wen, H. S., Li, X., Cao, Y. Z., Zhang, C. C., Yang, F., Shi, Y. M., & Peng, L. M. (2012). Clinical studies on the treatment of cancer cachexia with megestrol acetate plus thalidomide. Chemotherapy, 58, 461–467.

doi: 10.1159/000346446
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Study Purpose:

To confirm the effectiveness of the combination of megestrol acetate (MA) and thalidomide for the treatment of cancer cachexia.

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to receive either 160 mg of MA and 50 mg of thalidomide daily or MA alone for eight weeks. Study measures were obtained at baseline and eight weeks.

Sample Characteristics:

  • The sample was comprised of 93 patients (59% male, 41% female).
  • Mean age was 62 years.
  • Cancer diagnoses were various tumor types with stage III or IV disease, and 62% of the patients were receiving palliative chemotherapy.

Setting:

  • Single site
  • Outpatient
  • China

Phase of Care and Clinical Applications:

The study has clinical applicability for late effects, survivorship, and palliative care.

Study Design:

This was a randomized, parallel, two-group trial.

Measurement Instruments/Methods:

  • Body weight
  • Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF)
  • European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORT QLQ-C30)
  • Visual analog scale (VAS) for appetite
  • Grip strength dynamometry
  • Serum levels of interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNFα)
  • National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0

Results:

  • Both groups showed improvement in appetite (p < 0.01) and body weight (p = 0.02).
  • No significant difference was found between groups in change in appetite.
  • Patients receiving both MA and thalidomide showed significant reduction in fatigue, whereas those on MA only had increased fatigue (p < 0.01). 
  • Grip strength and IL-6 improved in the patients receiving both drugs compared to those receiving only MA (p < 0.05).
  • A portion (7.8%) of the initial sample withdrew because of severe side effects, such as thromboembolism. 
  • No difference was found between groups in prevalence of adverse effects.

Conclusions:

The combination of MA and thalidomide was associated with improvement in fatigue compared to those receiving only MA. The drug combination was not more effective in treating anorexia and did not show more improvement in body weight.

Limitations:

  • The sample size was small, with less than 100 patients.
  • The study had risks of bias due to having no control group or blinding.

Nursing Implications:

MA has been shown to have an effect in improving appetite in patients with cancer cachexia, but, as shown, also can have clinically significant side effects. Findings from this study did not show better results for appetite with the addition of thalidomide. This combination appeared to have a positive impact on fatigue. Nurses should be aware that patients taking MA can have side effects, such as thromboembolism, so patients receiving this treatment need to be educated and monitored for adverse events.

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.

doi: 10.1111/j.1365-2354.2011.01255.x
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Study Purpose:

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

Intervention Characteristics/Basic Study Process:

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.

Sample Characteristics:

  • 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.

Setting:

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

Phase of Care and Clinical Applications:

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

Study Design:

A randomized, placebo-controlled trial design was used.

Measurement Instruments/Methods:

  • 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

Results:

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.

Conclusions:

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.

Limitations:

  • 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.

Nursing Implications:

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.

Yennurajalingam, S., Willey, J.S., Palmer, J.L., Allo, J., Del Fabbro, E., Cohen, E.N., . . . Bruera, E. (2012). The role of thalidomide and placebo for the treatment of cancer-related anorexia-cachexia symptoms: Results of a double-blind placebo-controlled randomized study. Journal of Palliative Medicine, 15, 1059–1064.

doi: 10.1089/jpm.2012.0146
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Study Purpose:

To determine the effects of thalidomide on anorexia-cachexia and related symptoms

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive either 100 mg of thalidomide or placebo orally for 14 days. Pre- and post-study measurements were done.

Sample Characteristics:

  • A total of 21 patients completed the study.
  • Median patient age was 60 years, with a range of 24–81 years.
  • The sample was 59% male and 41% female.
  • Patients had multiple tumor types.
  • All patients had at least 5% weight loss in the past six months. All had to have anorexia and fatigue and at least one of the following symptoms within the preceding 24 hours: anxiety, depression, or sleep disturbance.
  • The sample was mostly Caucasian; 15% was African American and 9% was Hispanic.

Setting:

The study was conducted at a single site in an outpatient setting in Anderson, TX.

Phase of Care and Clinical Applications:

The study has clinical applicability for late effects and survivorship.

Study Design:

A randomized controlled trial design was used.

Measurement Instruments/Methods:

  • Edmonton Symptom Assessment Scale
  • Functional Assessment of Anorexia/Cachexia Therapy
  • Hospital Anxiety and Depression Scale
  • Pittsburgh Sleep Quality Index
  • Bioelectrical impedance
  • Cytokine levels

Results:

There was no significant change in appetite with thalidomide. Those receiving placebo had improvement in appetite at day 15 (p = 0.01). Body composition measures showed significant decline in body fat percent, fat mass, and fat-free mass by day 15 (p < 0.05), which reversed by day 29.

Conclusions:

The study did not demonstrate any benefit of thalidomide for anorexia or related symptoms.

Limitations:

  • The study had a small sample size, with less than 30 participants.
  • Findings are not generalizable.
  • Protocol fidelity was questionable. 
  • Participant withdrawals were 10% or greater.
  • The authors noted an approximate 30% drop-out rate and poor compliance of study participants.
  • Sample inclusion criteria were very restrictive.

Nursing Implications:

This study does not provide any conclusive findings due to the small sample size and other study limitations cited.


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