Transcript 8 L-Carnitine and Cancer Patients

L-Carnitine and Cancer Patients
Cancer & Metabolism
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In cancer patients, abnormalities of tumor tissue as well as non-tumor tissue
metabolism have been observed.
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Such abnormalities are supposed to contribute to deterioration of clinical status of
patients, or might induce carcinogenesis by themselves.
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The carnitine system appears affected both in tumor tissue, in such a way as to greatly
reduce fatty acid beta-oxidation, and in non-tumor tissue.
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It is known that cancer cells are developed deriving energy from glycolysis.
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One of the defensive mechanisms of the organism against this process is probably the
suppression of glycolysis with increasing production of energy through beta-oxidation.
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Beta-oxidation seems to play a protective role for the cancer-affected tissues, and
carnitine availability/deficiency is crucial for maintaining such process.
Rogalidou et al, 2007
OCTNs and Cancer
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Cancer cells shift from aerobic to anaerobic ATP production, bypassing the
mitochondrial function; this phenomenon is known as the Warburg effect.
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In other words, the energy in cancer cells comes mainly from anaerobic glycolysis and
amino acid oxidation rather than fatty acid-oxidation in mitochondria.
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The fatty acid oxidation is regulated in cells, among other factors, by carnitine
availability; in this scenario, carnitine homeostasis has been suggested to play a
regulatory function in the metabolic switch observed in cancer.
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Down-regulation of OCTN2 expression in several cancer cell lines has been reported.
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A link between OCTN1 and cancer has been also proposed.
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The transporter seems to be associated with sporadic colorectal cancer in early age,
and its polymorphisms, such as L503F, may help to predict malignant progression of
the disease in inflammatory bowel disease (IBD) patients.
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OCTN1 has been found to be overexpressed in tumors, being involved in the uptake of
anticancer drugs.
Pochini 2013
Carnitine loss with carboplatin treatment
LC
ALC
Urinary excretion
(µ moles/day)
1000
**
800
600
400
200
*
0
Day -1
* p<0.05; ** p<0.01
Mancinelli A et al. Cancer Chemother Pharmacol 2007; 60:19-26
Day 0
Day +1
Day +6
Total Carnitine plasma levels in chemotherapy
64.00
Total Carnitine levels
Group
60.00
Newly Diagnosed / No Prior
Chemotherapy
56.00
Prior Chemotherapy
52.00
48.00
44.00
40.00
36.00
Before
Before chemotherapy
After
Time (one week)
Newly Diagnosed / No Prior Chemotherapy Mean
(95% CI)
47.70 (42.88–52.51)
Prior Chemotherapy
Mean (95% CI)
47.52 (42.05–52.98)
57.12 (51.71–62.59)
46.00 (40.53–51.47)
One week after chemotherapy
Hockenberry MJ et al. J Pediatr Hematol Oncol 2009;31:664–669
Free Carnitine plasma levels in chemotherapy
58.00
Free Carnitine levels
Group
54.00
Newly Diagnosed / No Prior
Chemotherapy
50.00
Prior Chemotherapy
46.00
42.00
38.00
34.00
30.00
Before
Before chemotherapy
After
Time (1 week)
Newly Diagnosed / No Prior Chemotherapy Mean
(95% CI)
41.00 (36.67–45.33)
Prior Chemotherapy
Mean (95% CI)
41.55 (36.36–46.73)
50.59 (45.49–55.60)
40.12 (34.89–45.35)
One week after chemotherapy
Hockenberry MJ et al. J Pediatr Hematol Oncol 2009;31:664–669
Cancer fatigue
• Characterized by feelings of tiredness, weakness, and
lack of energy, distinct from the “normal” drowsiness
experienced by healthy individuals in that it is not
relieved by rest or sleep.
• It occurs both as a consequence of the cancer itself
and as a side effect of cancer treatment, although the
precise underlying pathophysiology is largely unknown.
Chemotherapy side effects
Hofman M et al. The Oncologist 2007;12:4-10.
Measuring cancer fatigue
• Visual Analog Scale (VAS)
• Brief Fatigue Inventory (BFI)
• The Functional Assessment of Cancer Therapy
instrument
• Multidimensional Fatigue Symptom Inventory-Short
Form
• Etc..
Multifactorial pathogenesis
Physiological factors
Sociodemographic Factors
Anemia
Age
Uremia
Sex
Hyperparathyroidism
Race
Medication
Employment Status
Inflammation
Marital Status
Physical Inactivity
Comorbidities
Physiological/ Behavioral
factors
Anxiety
Depression
Cancer
Fatigue
Education
Social Support
Cancer-Related Factors
Organ effect: pulmonary fibrosis,
myopaty, carnitine loss and
deficiency
Sleep Disorders
Pain and its treatment
Substance Use
Frequency of chemotherapy
Multi-disciplinary approaches to improve
cancer fatigue
Targeted area
Interventions
Increase health care provider
awareness
• Education of prevalence, importance and severity of
fatigue
• Training at identifying symptoms of fatigue
Improve measurement of fatigue
• Development of criteria for defining fatigue
• Development of improved fatigue scales
• Use of ecological momentary assessment for
measurement of day-to-day and diurnal variation in
fatigue
• Development of improved survey modalities such as
telephone interview, computer-assisted interview,
and proxy administration of interviews to reduce
selection bias
• Frequent screening for fatigue
Address gaps in understanding
pathogenesis of fatigue
• Role of cytokines
Jham M et al. 2008 Am J Kidney Dis, 55(2):353-365
Multi-disciplinary approaches to improve
cancer fatigue
Targeted area
Interventions
Test potential therapies for
fatigue
Non-pharmacological
• Nutritional therapy
• Sleep therapy and sleep hygiene
• Exercise
• Stress management
• Cognitive-behavioral treatment of depression
• Energy Conservation
• Acupressure
• Treatment of substance abuse and dependence
Pharmacological
• Hematopoeitics
• Antidepressants
• Anxiolytics
• Levocarnitine
• Human growth hormone
Improving social support for
patients with fatigue
• Family members and care providers education and
training
• Addressing caregiver fatigue
• Frequent screening for fatigue
Multi-disciplinary approaches to improve
cancer fatigue
Targeted area
Interventions
Test potential therapies for
fatigue
Non-pharmacological
• Nutritional therapy
• Sleep therapy and sleep hygiene
• Exercise
• Stress management
• Cognitive-behavioral treatment of depression
• Energy Conservation
• Acupressure
• Treatment of substance abuse and dependence
Pharmacological
• Hematopoeitics
• Antidepressants
• Anxiolytics
• Levocarnitine
• Human growth hormone
Improving social support for
patients with fatigue
• Family members and care providers education and
training
• Addressing caregiver fatigue
• Frequent screening for fatigue
L-Carnitine reduces cancer fatigue
Brief Fatigue Inventory (BFI) Scores before and after L-Carnitine
80
70
60
50
40
30
20
10
0
Median BFI Score
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**
*
Pre
All patients (ITT, n = 27)
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Post
Responders (n = 17)
Cruciani et al., Journal of Pain and Symptom Management 2006; 32(5):551-559
* p < 0.001
**p < 0.001
L-Carnitine improves the
Depressed Mood
Center for Epidemiologica Studies-Depression (CES-D) Scores before and after L-Carnitine
80
70
60
50
40
30
20
10
0
Median CES-D Score
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*
*
**
Pre
All patients (ITT, n = 27)
Post
Responders (n = 17)
Cruciani et al., Journal of Pain and Symptom Management 2006; 32(5):551-559
* p < 0.001
** p = 0.001
Results: Quality of Sleep (ESS)
Comparisons of ESS Scores before and after L-Carnitine supplementation.
80
70
60
50
40
30
20
10
0
Median ESS Score
*
**
*
Pre
All patients (ITT, n = 27)
**
Post
Responders (n = 17)
Cruciani et al., Journal of Pain and Symptom Management 2006; 32(5):551-559
* p = 0.001
**p = 0.003
Results: Fatigue Dose Response
L-Carnitine Dose Response for Fatigue (Brief Fatigue Inventory score)
100
Free carnitine
Total carnitine
BFI
Mean
80
60
40
20
0
250
750
1250
1750
2250
2750
Dose of L-Carnitine (mg/day)
3000
Analysis of the 17 patients, who after 1-week supplementation, had increased serum carnitine levels (“responders“).
Each bar represents a dosing group. There was significant dose response for total carnitine (r = 0.54, p = 0.03) and for free carnitine (r = 0.56, p = 0.02).
Decrease in fatigue scores (BFI) also showed a significant dose response (r = -0.61, p = 0.01).
Cruciani et al., Journal of Pain and Symptom Management 2006; 32(5):551-559
L-Carnitine reduces cancer fatigue
Multidimensional Fatigue Symptom Inventory – Short Form questionnaire
Mean Scores
Mean Subscale Scores
30
25
20
15
10
5
0
p < 0.05
p < 0.001
t0
t1
t2
• Fatigue reduced significantly after
2 weeks (t1 p < 0.05) and 4 weeks (t1 p < 0.001)
treatment with 6g oral L-Carnitine.
Gramignano G et al., Nutrition 2006; 22: 136-145
Gramignano G et al., Nutrition 2006; 22: 136-145
10
8
6
4
2
0
-2
-4
-6
-8
t0
t1
t2
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* p < 0.05. T2, 2 week of treatment.
General
Physical
Emotional
Mental
Vigor
Evaluation of the General, Physical, Emotional, Mental and Vigor subscales showed a
statistically significant difference between
baseline (t0) and 4 wk(t2) of treatment for both the general scale
(p < 0.05) and the physical scale (p < 0.05).
L-Carnitine improves Quality of Life
• Quality of Life improved significantly according to both QoL-OS and EQ-5DVAS
QoL-OS Scores
30
25
EQ-5DVAS Score
t0
t1
t2
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20
15
* p < 0.05
10
5
*
*
*
*
0
Functional
Physical
Social/Family
Emotional
Fatigue
Histograms represent the mean scores of part A subscales of the questionnaire on quality of life with a focus on oxidative
stress (Functional, Physical, Emotional, Social and Family and Fatigue). Evaluation of the subscale scores showed a
statistically significant difference between mean values at baseline (t0) versus w week (t2) of treatment (p < 0.05) in each
subscale.
Gramignano G et al., Nutrition 2006; 22: 136-145
Gramignano G et al., Nutrition 2006; 22: 136-145
80
70
60
50
40
30
20
10
0
p < 0.001
p < 0.05
t0
t1
t2
Histograms represent the mean scores of the EQ-5D visual analog scale. The difference
between the mean score at baseline (t0) and after 2 weeks (t1) and 4 weeks (t2) of treatment with L-Camitine
supplementation was statistically significant for t1 and t2 versus t0 (p < 0.05 and p < 0.001, respectively).
L-carnitine on cancer fatigue
Main Clinical Trials
No. and type
of patients
LC Dose
Results
12, advanced tumour
Gramignano 2006
6 g/day os
4 weeks
Fatigue decreased significantly, particularly for the General and Physical
scales and quality of life. Lean body mass and appetite increased
significantly. Levels of reactive oxygen species decreased and glutathione
peroxidase increased
50,
Graziano 2002
4 g/day os
7 days
Fatigue ameliorated in 45 patients and the mean
Functional Assessment of Cancer Therapy-Fatigue score was 34.9 (± 5.4;
standard deviation) (p < 0.001). All patients achieved normal plasma
carnitine levels.
9, solid or haematological
tumours undergoing anthracycline
therapy
De Leonardis 1985
3 g/day os
3 days before treatment
LC treatment reduce anthracycline-dependent acute
cardiotoxicity and also positively affect the cardiac
contractility during chemotherapy.
1 g iv
day of treatment
3 g/dayos
3 days after treatment
104, advanced gynecological
cancer
Macciò 2012
4 g/day os
4 months
Improvement of lean body mass, resting energy expenditure, fatigue, and
global quality of life.
60, cancer-related
anorexia/cachexia syndrome
Madeddu 2012
4 g/day os
4 months
Significant improvement of lean body mass and physical performance.
L-Carnitine-supplementation in advanced
pancreatic cancer (CARPAN) - a randomized
multicentre trial
Kraft 2012
L-Carnitine-supplementation in advanced
pancreatic cancer (CARPAN) - a randomized
multicentre trial
Kraft 2012
L-Carnitine in Cancer Patients
• Reverts carnitine deficiency
• Improves chemotherapy-induced cancer fatigue
• Reduces anthracycline-dependent acute cardiotoxicity
• Improves:
– fatigue
– lean body mass,
– resting energy expenditure
– global quality of life.
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