Lucia Zappi
IRCCS Università San Martino IST
[email protected]
“…tutto
e’ una grande
fatica. Sembra assurdo
ma anche solo
pettinarmi o vestirmi
richiede uno sforzo
immane. Scendere dal
letto o andare al bagno è
il massimo che possa
fare. Fare le faccende è
veramente troppo: non
sarei neppure capace di
sollevare
l’aspirapolvere…”
NCCN
Definizione
Cancer related fatigue is a distressing
persistent, subjective sense of physical,
emotional and/or cognitive tiredness or
exhaustion related to cancer or cancer
treatment that is not proportional to recent
activity and interferes with usual functioning
La cancer-related fatigue è stata riconosciuta come
entità nosologica a sé stante dalla ICD 10
(X classificazione internazionale delle malattie)
Incidenza
78-96% della popolazione oncologica
 50% prima del trattamento

Aumenta durante il trattamento e persiste
anche dopo la terapia (17- 30% dei
survivors)
Incidenza trattamento correlata
Chemioterapia
 Radioterapia
 Immunoterapia

60-90%
65-100%
70-81%
Classificazione
GRADO 1
GRADO 2
GRADO 3
GRADO 4
Fatigue
ingravescente
ma non
interferenza con
le normali
attività
Moderata,
incapacità a
svolgere alcune
attività
Severa,
incapacità a
svolgere gran
parte delle
attività
Allettamento
Grave disabilità
NCI CTC 2004
The impact of fatigue
results of a survey by the Fatigue Coalition
Physical Impact
Financial Impact
Difficulty in carryng out
tasks, 56%
71% of patients lost one 59% reported difficulty in
or more days of work
socializing with friends and
family
Difficulty in climbing
stairs, 56%
31% lost an entire week 37% had difficulty in
of work
maintaing relationships
Difficulty in walking long 28% had to stop work
distance, 69%
Social and Emotional
Impact
30% found intercourse with
partner difficult
Difficulty in continuing
exercise, 67%
A. Iop, Ann Oncol 2004
RILEVANZA CLINICA DELLA
FATIGUE
L’importanza del trattamento di questo sintomo viene percepita
in modo differente dal medico rispetto al paziente
Fatigue
Dolore
Pazienti
Entrambi, allo stesso modo
Oncologi
0
20
40
60
80
Risposta (%)
Vogelzang NJ et al. Semin Hematol 1997; 34 (Suppl 2): 4-12
100
Although fatigue is usually the most commonly reported
adverse symptom during cancer therapy, up until
recently, there was little effort directed at reducing
fatigue before, during, or after cancer therapy
Von Roenn, J. H., & Paice, J. A.
Control of common, non-pain cancer symptoms.
Seminars in Oncology, 32, 200–210 - 2005
For clinical interventions to be effective, patients
with fatigue who would benefit from treatment must
first be identified
Vogelzang et al (1997) interviewed 419 cancer
patients:
50% did not discuss treatment options for fatigue
with their oncologists
only 27% reported that their oncologist offered
treatment recommendations for their fatigue
Curt et al (2000) similarly reported that 40% of
patients with fatigue did not receive any treatment
recommendations.
Fatigue assessment
• fatigue severity, temporal characteristics (e.g. onset,
duration)
• exacerbating and alleviating factors
• impact on functioning and quality of life symptomrelated distress
• other symptoms : pain, menopausal symptoms,
sleep disturbances, depression and cognitive
dysfunction
Since fatigue is a subjective sensation, it is
important to use validated, standardised
assessment instruments.
Direct effects of cancer
and tumour burden
Comorbid medical
conditions
• Anemia
• Malnutrition
• Thyroid dysfunction
• Infection
Exacerbating comorbid
symptoms
• Chronic pain
• Sleep disturbances
• Deconditioning
CANCER
RELATED
FATIGUE
Treatment side effects
• Chemotherapy
• Radiotherapy
• Surgery
• Medication sid effects
Psychosocial factors
• Coping with chronic illness
• Anxiety
• Depression
Causes of fatigue (Atkinson et al, 2002; Cella et al, 1998; Portenoy and Itri, 1999).
Meccanismi fisiopatologici
Peripheral fatigue
originates in the muscles and related tissues( alterations in
adenosine triphosphate - ATP)
Central fatigue
develops in the central nervous system
Proposed mechanisms
cytokine dysregulation,
hypothalamic-pituitary-adrenal (HPA) axis dysfunction,
5 hydroxy tryptophan (5-HT) neurotransmitter
dysregulation,
circadian rhythm disruption,
and vagal afferent activation
Cytokine Dysregulation
Proinflammatory cytokines such as interleukin (IL)-1β, IL6, and tumor necrosis factor (TNF)-α have been
evaluated as markers of cancer-related fatigue




Specific cytokines may contribute to fatigue
through more specific pathways:
IL-1 and IL-6 and TNF-α, have been shown to
suppress erythropoiesis,
TNF has been associated with alterations in
central nervous system neurotransmission
interferon-γ can act as chachectins
IL-6 have also been associated with depression
Interventions








pharmacological interventions
exercise
behavioural management
use of assistive devices
lifestyle management
nutritional support
complementary or alternative therapy
counselling
NCCN Guidelines
Activity enhancement
Anne-Marie Kuchinski
MEDSURG Nursing—May/June 2009—Vol. 18/No. 3
Treatment-Related Fatigue and Exercise in Patients with
Cancer: A Systematic Review
January 2000 and October 2006
English
peer- reviewed nursing and health care journals
age 18 or older
literature search conducted in October 2006 using the
CINAHL®, Medline®, Ovid®, and ProQuest®
databases
topics: fatigue, cancer, and exercise
Results:
10 studies
Sample size ranged from 12 to 108
Level of evidence: moderate to high
Anne-Marie Kuchinski
MEDSURG Nursing—May/June 2009—Vol. 18/No. 3
focused question :
“What is the relationship
between cancer treatment fatigue
and exercise?”
Anne-Marie Kuchinski
MEDSURG Nursing—May/June 2009—Vol. 18/No. 3
This systematic review considered the effect of
exercise on fatigue in patients with
multiple myeloma
breast
lung
prostate cancers
both early and late stages of disease
patients receiving chemotherapy or radiation
setting of interventions
home-based exercises (8 )
 out-of home exercises (2)

Home-based exercise interventions
walking
bicycling or swimming
RESULTS
 improvement in vigor and reduction in fatigue, with a
trend toward improved body esteem Pinto 2005
 improved sleep, increased lean body weight, and less
fatigue with exercise Coleman 2003
 progressively increased time in minutes walked per day
 improved QOL and a significant decrease of fatigue
Courneya 2003
 moderated aerobic exercise and resistance training
decreased the overall perception of fatigue Crowley
2003
Out of home exercise interventions
Controlled setting with professional instructors with a focus on
muscle strengthening, flexibility, and endurance.
Researchers found exercise to be well-tolerated and
feasible in a variety of malignancies.
 No noticeable change in fatigue occurred, but reported
bodily pain decreased Losito, Murphy, & Thomas, 2006
 Improved physical and emotional well-being Borst 2005
Participation in a group exercise program was
beneficial because patient support increased
motivation.
Conclusions
Patients with cancer may be challenged to initiate
and maintain an exercise program for more than 3
months without unswerving professional support
This support can be made more effective if the
recommended exercise program is regularly
adjusted to the patients’ health status and
considers shifting hemoglobin levels, vital signs,
respiratory health, and subjective feelings that
influence the outcomes of exercise
Fatigue and the nutritional approaches
At the organism level, cancer-associated
fatigue involves the dysregulation of
several interrelated physiological,
biochemical, and psychological systems
At the tissue and cellular levels, fatigue is
related to reductions in the efficiency of
cellular energy systems, mainly found in
mitochondria
Oxidative stress: intracellular excess of reactive
oxygen (ROS) and nitrogen (RNS) free radical
species over intracellular antioxidants
It results in oxidation of cellular structures
such as membrane lipids and proteins, and
mutation of nuclear DNA
Maes, M. (2009). Inflammatory and oxidative and nitrosative
stress pathways underpinning chronic fatigue, somatization
and psychosomatic symptoms. Current Opinions in
Psychiatry, 22, 75–83
ROS/RNS damage
Membrane oxidation
induces permeability
changes in
mitochondria, and this
loss of electron
transport function
essential requirement
of mitochondrial
oxidative
phosphorylation (ATP)
I Nutraceutici
Acidi grassi polinsaturi essenziali (Omega 3 /
Omega 6), Acido Antranilico, Acido ascorbico (o
Vitamina C), Acido Folico (o Folacina o Vitamina M),
Acido Lipoico (o Acido Tiottico o Vitamina N),
Antocianine (o Antociani), Bioflavonoidi o
(Flavonoidi o Vitamina C2), Caffeina, L-Carnitina,
Carotenoidi, Coenzima Q-10 (o Ubichinone o
Vitamina Q), Colina (o Vitamina J), Creatina, Dribosio, Ficocianine, Fruttosio, Glucosammina,
Inositolo (o Vitamina B7), Isoflavoni, Licopene,
Lievito di birra, Maltodestrine, Octacosanolo,
Picnogenolo, Policosanoli, Proantocianidine (o
PAC), Probiotici, Resveratrolo, Sali minerali (Calcio,
Cromo, Fluoro, Fosforo, Iodio, Magnesio, Potassio,
Ferro, Selenio, Sodio, Zinco), Steroli vegetali (o
Fitosteroli), Taurina, Teanina, Teina, Triptofano,
Vitamine, 5-HTP (5-idrossitriptofano)
Lipid replacement therapy
NTFactor®,
a lipid replacement oral
supplement
containing
phospholipids,
phosphoglycolipids,
cardiolipids,
and other
membrane lipids
Ellithorpe, R. R., Settineri, R., & Nicolson, G. L. (2003).
Reduction of fatigue by use of a dietary supplement containing
glycophospholipids. Journal of the American Nutraceutical Association,
6(1), 23–28.
NTFactor in patients
with severe chronic
fatigue
 reduce their fatigue
by approximately
40.5% in 8 weeks

40,5 %
Nicolson, G. L., Ellithorpe, et al.
Lipid replacement therapy with a glycophospholipid– antioxidant–
vitamin formulation significantly reduces fatigue within one week.
Journal of the American Nutraceutical Association, 13(1), 11–15. 2010
NTFactor plus
vitamins, minerals,
and other
supplements
 resulted in a 36.8%
reduction in fatigue
within 1 week

Safety, Tolerability and Symptom Outcomes Associated with L-Carnitine
Supplementation in Patients with Cancer, Fatigue, and Carnitine Deficiency:
A Phase I/II Study
Ricardo A. Cruciani, 2006 Journal of Pain and Symptom Management
L-carnitine, a micronutrient
important for the
processing of long-chain
fatty acids and energy
production in mammalian
cells
Dose escalation
proceeded through all dose
levels (250, 750, 1250,
1750, 2250, 2750, and
3000 mg/day,respectively)
mild nausea
no other side effects
Pharmacologic Treatment of Cancer-Related Fatigue
Jennifer K. Carroll The Oncologist 2007;12;43-51;

L-carnitine
three studies
open-label prospective designs with 12–50
participants
Treatment with l-carnitine (500–600 mg/day) for 1–4
weeks

RESULTS:
increased plasma free carnitine concentrations
significantly improved fatigue and quality-of-life
measures
Efficacy of l-carnitine administration on fatigue, nutritional
status, oxidative stress, and related quality of life in 12
advanced cancer patients undergoing anticancer therapy
Giulia Gramignano, Nutrition Volume 22, February 2006
12 patients
advanced tumors (50% at stage IV)
mean age 60 y, range 42–73
antineoplastic treatment
L-Carnitina was administered orally at 6 g/d for 4 wk
outcome measures: fatigue and quality of life in
relation to oxidative stress, nutritional status, and
laboratory variables (reactive oxygen species,
glutathione peroxidase, and proinflammatory
cytokines)
Giulia Gramignano, Nutrition Volume 22, February 2006
RESULTS:
Fatigue decreased significantly
Nutritional variables (lean body mass and appetite)
increased significantly
Levels of reactive oxygen species decreased and
glutathione peroxidase increased but not
significantly
Proinflammatory cytokines did not change
significantly
Reversing mitochondrial dysfunction, fatigue and the adverse effects
of chemotherapy of metastatic disease by molecular replacement
therapy
Clin Exp Metastasis (2008) 25:161–169
Garth L. Nicolson Æ Kenneth A. Conklin

Chemotherapy can displace
important mitochondrial
cofactors, such as CoQ10

The concurrent administration
of CoQ10 during chemotherapy
can affect both acute and
chronic cardiotoxicity caused
by anthracyclines

Acute and chronic adverse
effects of cancer chemotherapy
can be reduced by molecular
replacement of membrane
lipids and enzymatic cofactors,
such as coenzyme Q10
Neuro Endocrinol Lett. 2005 Dec;26(6):745-51.
In chronic fatigue syndrome, the decreased levels of
omega-3 poly-unsaturated fatty acids are related to
lowered serum zinc and defects in T cell activation
Maes M, Mihaylova I, Leunis JC.

omega3 poly-unsaturated fatty acids (PUFA):
eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA)

CFS was accompanied by increased levels of omega6
PUFAs
linoleic acid
arachidonic acid (AA)
mono-unsaturated fatty acids (MUFAs), i.e oleic acid
ω6-PUFA
ω3-PUFA
Acido Linoleico
Acido Linolenico
Acido Eicosapentaenoico e
decosaesaenoico
Acido Arachidonico
Fosfolipidi di membrana
Fosfolipasi A2 e C
Lipoossigenasi
Ac. Arachidonico
libero
Lipoossigenasi
LT
Serie 4
Immunosoppressione
Radicali Liberi
Carcinogenesi
PG
serie 2
Cicloossogenasi
Prostanoidi
Serie 2
TX
Serie 2
LT
Serie 5
Cicloossogenasi
Prostanoidi
Prostanoidi
Serie 33
Serie
Diminuzione attivazione piastrine
Vasodilatazione
Inibizione cascata infiammazione
Neuro Endocrinol Lett. 2005 Dec;26(6):745-51.
Maes M, Mihaylova I, Leunis JC.
Results:
decreased availability of omega3 PUFAs plays a
role in the pathophysiology of CFS and is related
to the immune pathophysiology of CFS.
The results suggest that patients with CFS should
respond favourably to treatment with omega3
PUFAs, such as EPA and DHA
Serotonin and central nervous system fatigue:
nutritional considerations
J Mark Davis Am J Clin Nutr 2000;72(suppl):573S–8S
Increases in brain 5-HT concentration have been
associated with increased physical and perhaps
mental fatigue during endurance exercise
Carbohydrate (CHO) or branched-chain amino acid
(BCAA) feedings may attenuate increases in 5-HT
and improve performance
Good theoretical rationale and data exist but the
strength of evidence is presently weak
Cochrane Database of Systematic
Reviews 2012
Types of participants
Adults 18 years or older
Advanced progressive illness
Clinically significant fatigue and/or weight loss in the
latter stages of illness:




degenerative neurological conditions, such as
multiple sclerosis, Parkinson’s disease and
dementia
irreversible organ failure
cancer with distant metastasis
acquired immune deficiency syndrome
Cancer - identified five systematic reviews
(116 studies with 17,342 participants)
• pharmacological interventions :
eicosapentaenoic acid (EPA), amantadina,
carnitina,eritropoietina
• non pharmacological interventions:
exercise, physical training, medically assisted
hydration, psychosocial interventions
Types of outcome measure
Primary outcomes:
1. Clinically significant improvements in fatigue
2. Improvements in quality of life
3. Withdrawals due to adverse events
Cancer fatigue
Pharmacological interventions
RESULTS
Dewey 2007 (five studies, 587 participants)
failed to provide sufficient evidence of a benefit to
the use of EPA (ac. Eicosapentaenoico) over
placebo for the management of fatigue in
advanced cancer
Cancer fatigue
Pharmacological interventions
RESULTS
Minton 2008 (51 studies, 10,296 participants)
small but significant improvement in fatigue over
placebo with the psychostimulant drug
methylphenidate.
Cancer fatigue
Pharmacological interventions
RESULTS
Glaspy 2010
Although erythropoietin and darbepoetin showed
evidence of an effect over standard care or
placebo
they are no longer recommended in practice for
this use, especially if haemoglobin concentration
is above 12 g/dL
Cancer fatigue
Pharmacological interventions
RESULTS
No benefits over placebo were seen for fatigue with
the use of the antidepressant drug paroxetine, nor
with progestational steroids.
Megestrol acetate can provide a small, statistically
significant weight gain for people with cancer
versus placebo
Cancer fatigue
Non pharmacological interventions
RESULTS
Cramp 2008 (28 studies, 2083 participants)
supported the use of exercise in the management
of cancer related fatigue
No recommendations can be made for specific
exercise interventions that might best manage
fatigue in advanced stages of cancer.
The optimal management of fatigue is likely
to be different for those in the advanced stages of
a non curative illness as compared with those
who are in the early stages of chronic disease
Cancer fatigue
Non pharmacological interventions
RESULTS
Goedendorp 2009 (27 studies with 3324 participants)
For people undergoing cancer treatment at any
disease stage found
Insufficient evidence that psychosocial
interventions were beneficial for fatigue
management
I’m so Tired: Biological and Genetic Mechanisms of
Cancer related Fatigue
Andrea Barsevick, PhD, Qual Life Res. 2010 December ; 19(10):
1419–1427.
As the science continues
to progress toward
individualized
medicine,
understanding the
genetic dimensions of
CRF will become
increasingly important
in order to identify
persons at risk for this
debilitating symptom
as well as targets
for intervention to
alleviate it