Carnitine/L-Carnitine

Carnitine/L-Carnitine

PEP Topic 
Anorexia
Description 

Acetyl-l-carnitine (γ-trimethyl-β-acetylbutyrobetaine, or ALC) is the acetyl ester of carnitine. ALC is present throughout the central and peripheral nervous systems, plays an essential role in the oxidation of free fatty acids, and has displayed neuroprotective properties. Carnitine is available without a prescription as a dietary supplement, and is found in highest concentrations in red meat and dairy products.

Effectiveness Unlikely

Research Evidence Summaries

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.

doi: 10.1016/j.ygyno.2011.12.435
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Study Purpose:

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

Intervention Characteristics/Basic Study Process:

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.

Sample Characteristics:

  • 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.

Setting:

This multisite study was conducted in an inpatient setting in Italy.

Phase of Care and Clinical Applications:

  • 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.

Study Design:

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

Measurement Instruments/Methods:

  • 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

Results:

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.

Conclusions:

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.

Limitations:

  • 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.

Nursing Implications:

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

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.

doi: 10.1016/j.clnu.2011.10.005
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Study Purpose:

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

Intervention Characteristics/Basic Study Process:

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.

Sample Characteristics:

  • 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.

Setting:

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

Phase of Care and Clinical Applications:

  • 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.

Study Design:

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

Measurement Instruments/Methods:

  • 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

Results:

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.

Conclusions:

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

Limitations:

  • 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.

Nursing Implications:

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.

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
Print

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.


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