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Scuola Mediterranea di Oncologia
“Actigrafia nel tumore della mammella”
Roma 28.11.2008
Dott. Carlo Garufi
Oncologia Medica C
Istituto Regina Elena, Roma
BREAST CANCER
• Fatigue is the most prevalent and distressing
symptom experienced by pts receiving
adjuvant ChT for early stage BC
• Higher fatigue levels are related to sleep
maintenance problems and low daytime
activity in pts after ChT
• Sparse data available about circadiam
rhythms alteration and fatigue prior to
chemotherapy
Is the doctor’s view a reliable measure of patients HRQOL?
Ample evidence suggest doctors
might systematically misjudge
patients' perception levels of
symptoms or related important
aspects of their illness….and there
is wide agreement that patient
themselves should be the primary
source of information.
(Slevin et al 1988; Sprangers et al. 1992; Da Silva et al. 1996;
Stephens et al. 1997 Passik et al. 1998; Fayers et al. 2000;
Wilson et al. 2000; Titzer et al. 2001)
http://www.ispor.org/Meetings/va0502/symposium.asp
Cancer Related Fatigue
“distressing, persistent, subjective, sense of
tiredness or exhaustion related to cancer
or to cancer treatment that is not
proportional to recent activity and
interferes with usual functioning”
NCCN 2006
(Cleeland, et al, 2004)
Pain
Lower sleep quality
Anxiety
Cancer Related Fatigue
Physical Inactivity
Poor PS
REST/ACTIVITY RHYTHM: THE ACTIGRAPH
Piezo-electric accelerometer;
Number of wrist accel./minute;
Allows continuous recording,
over a long time period.
Parameters:
24-h pattern and
alternance of rest and activity.
Independent prognostic value of the rest/activity circadian rhythm on overall
survival (OS) in patients (pts) with metastatic colorectal cancer (MCC) receiving
first line chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin: a
companion study to EORTC 05963.
C. Garufi et al. ASCO 2005
The data confirmed the strong and indipendent prognostic value
of the RAR for the survival of MCC patients in a multicentre
randomized trial
Quality of life (QoL) correlates with the rest/activity circadian rhythm
(RAR) in patients (pts) with metastatic colorectal cancer (MCC) on first
line chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin : an
international multicenter study (EORTC 05963).
P.F. Innominato et al. ASCO 2005
The correlation
between RAR and
Global QoL and
symptom scores as
fatigue and anorexia
was confirmed
for the first time in a
multicenter setting
Studi di Cronotherapia presso l’IRE
5FU/FA
Garufi et al
EJC ‘97
5FU/FA
FFL
Garufi et al Anticancer Drugs ‘01
CPT-11 + FF 5-16
Garufi et al Cancer ‘01
CPT-11 crono vs
standard + FF 4-10
Garufi et al EJC ’06
CPT-11 bolus + FFL crono
Garufi et al BJC ‘03
EORTC 05011
CPT-11 + FFL
Analisi Univariata e Multivariata sec Cox per la Sopravvivenza
Variables
Hazard ratio (HR)
95% Confidence Interval
P-value
UNIVARIATE
Sex
0.677
0.462-0.991
0.04
Performance Status
0.277
0.163-0.469
<0.0001
Age
n.s.
Site of primary tumor
n.s
Number site involved
0.605
0.402-0.911
0.01
Physical Functionig
0.988
0.979-0.996
0.004
Emotional Functioning
0.99
0.982-0.998
0.01
Social Functioning
0.992
0.923-1.000
0.04
Fatigue
1.014
1.007-1.021
<0.0001
Pain
1.011
1.004-1.018
0.002
Nausea/vomiting
n.s.
Appetite Loss
1.007
1.000-1.014
0.04
Costipation
n.s.
Diarrhoea
n.s.
Global QoL
0.978
0.970-0.986
<0.0001
Performance Status
0.387
0.221-0.677
<0.0001
Global QoL
0.977
0.969-0.986
<0.0001
Qol parameters
MULTIVARIATE
Correlation: Rest/activity and Cortisol rhythms,
TGF- and cytokines, and symptoms.
Individual patient
circadian rhythm
assessment by
actigraphy.
Cortisol
Ratio
(Slope)
Serum
TGF-
Serum Symptoms
IL-6
Robust Rhythm *
(autocorrelation
>0.47)
1.72
(Steep)
Low
Low
Less fatigue,
appetite loss.
High
High
More fatigue
and appetite
loss.
Dampened Rhythm 1.60
(autocorrelation
(Flat)
<0.35)
* p = < 0.05
Clin Cancer Res 2005; 11(5):1757-1764
Study
Population
Study timing
Variable
Methods
Findings
Ancoli-Israel
2006
n=85 (34-79y)
Stage I-III
Prior ChT
Fatigue
Obj/Subj sleep quality
Circadian rhythm
MFSI, PSQI
Actigraph
Andrykowski
1998
n=88 (35-76y)
Stage I-IIIA
After ChT
Fatigue
Sleep quality
CFS, PFS, PSQI
Berger
1998
n=72 (33-69y)
Stage I/II
During ChT
Fatigue
Activity and rest cycle
PFS
Actigraph
Fatigue and disrupted activity/sleep
inversely related (p<.05)
Berger
1999
n=72 (33-69y)
Stage I/II
During ChT
Fatigue
Circadian activity/rest
indicators
PFS
Actigraph
Reduced daytime activity, increased
daytime sleep, and increase nighttime
awakening were associated with
increased fatigue
Berger
2000
n=14 (32-69y)
Stage I/II
During/ after ChT
Fatigue
Activity and rest cycle
Actigraph, MSD,
SES, PFS
Low activity, disrupted sleep and
increased distress werecorrelated with
fatigue
Bower
2000
n=1957 (mean
55y) Stage 0III
After ChT
Fatigue
Sleep disturbance
Energy fatigue
subscale MOSSS
Fatigue is strongly associated with
sleep disturbance
Broeckel
1998
n=61 (29-75y)
After ChT
Fatigue
Sleep quality
FS from PMS,
PSQI
Severe fatigue significantly correlates
with poorer sleep quality (p<.05) and
sleeping during the day (p<.001)
Curran
2004
n=25 (28-63y)
Stage 0-III
After ChT
Fatigue
Sleep duration
Likert scale, diary
sleep duration
Fatigue after treatmento not correlates
with sleep duration
Jacobsen
1999
n=54 (28-77y)
stage I-III
During ChT
Fatigue
Sleep problems
MSAS
Sleep problems associated with
significant increase in fatigue severity
Okuyama
2000
n=134 (28-86y)
Stage 0-III
After surg, ChT,
RT
Fatigue
Sleep
CFS, Likert scale
Insufficient sleep is one of the
determinat of fatigue
Roscoe
2002
n=78 (34-79y)
During Cht
Fatigue
Circadian sleep rhythm
FSC
Actigraph
Increased circadian rhythms disruption
correlates with increased fatigue
Significant correlation (p>.0001)
between subjective measure of sleep
and fatigue
Significant correlation between fatigue
and sleep quality
• 85 women with stage I-IIIA breast cancer
• evaluation 7 days prior adjuv (n=72) or neoadjuv (n=13) ChT
 Women report fatigue and disturbed sleep
before ChT begins
 Significant relationship between subjective
poor sleep and fatigue and/or reduction of
functional outcome
 Objective measures confirm disrupted and
disturbed sleep
 However no significant correlation between
objective sleep variable at night or during the
day and fatigue and/or functional outcome
Although their circadian rhythms are robust,
pts with more delayed rhythms experience more
daily disfunction secondary to fatigue
Supp Care Cancer 2006, 12: 201-9
 Possible correlation between depression and
fatigue
• 219 women with stage I-IIIA breast cancer
• Evaluation 48 h prior adjuvant ChT
• Measure of sleep (PSQI), fatigue (PFS) and circadian rhythms
(Actigraph)
J Pain Sympt Manag 2007, 33: 398-409
Berger et al., J Pain Sympt Manag 2007
Circadian
rhythm
Fatigue
Depression
Mood
Change in the actigraphy measures over time were significantly
correlated with chenges in fatigue, mood, and depression
Supp Care Cancer 2002, 10: 329-336
Roscoe et al., Supp Care Cancer 2002
Conclusions
• Fatigue
correlates
with
sleep
distrubance
• Actigraph can be used to monitor
circadian rhythms alteration
• Strategy of intervention through light
exposure or phisical activity could help
in preventing CRF