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CANCER FATIGUE
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..
Campos et al Annals of Oncology 2010
Multifactorial pathogenesis
Physiological factors
Sociodemographic
Factors
Anemia
Age
Uremia
Sex
Hyperparathyroidism
Race
Medication
Employment Status
Inflammation
Physical Inactivity
Comorbidities
Cancer
Fatigue
Marital Status
Education
Social Support
Physiological/ Behavioral
factors
Anxiety
Depression
Sleep Disorders
Substance Use
Cancer-Related Factors
Organ effect: pulmonary
fibrosis, myopaty,
carnitine loss and
deficiency
Pain and its treatment
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
Carnitine loss with carboplatin treatment
LC
ALC
Urinary excretion
(µ moles/day)
1000
**
800
600
400
200
*
0
Day -1
Day 0
* p<0.05; ** p<0.01
Mancinelli A et al. Cancer Chemother Pharmacol 2007; 60:19-26
Day +1
Day +6
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
One week after chemotherapy
Time (1 week)
After
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)
Hockenberry MJ et al. J Pediatr Hematol Oncol 2009;31:664–669
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
One week after chemotherapy
Time (one week)
After
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)
Hockenberry MJ et al. J Pediatr Hematol Oncol 2009;31:664–669
L-Carnitine reduces cancer fatigue
Brief Fatigue Inventory (BFI) Scores before and after L-Carnitine
Median BFI Score
80
70
*
**
*
**
60
50
40
30
20
10
0
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
L-Carnitine improves the
Depressed Mood
Center for Epidemiologica Studies-Depression (CES-D) Scores before and after L-Carnitine
Median CES-D Score
80
70
60
50
40
30
20
**
*
*
**
10
0
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.
Median ESS Score
80
70
60
50
40
30
20
*
**
*
**
10
0
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
3000
Dose of L-Carnitine (mg/day)
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
p < 0.05
20
p < 0.001
15
10
5
0
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
*
*
* 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
EQ-5DVAS Score
30
25
80
t0
t1
t2
70
*
20
15
10
*
60
50
20
10
*
*
p < 0.05
40
30
* p < 0.05
5
p < 0.001
*
0
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
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.