Dott. Carlo Garufi Oncologia Medica CIstituto Regina Elena, Roma

Scuola Mediterranea di Oncologia

“Actigrafia nel tumore della mammella”

Roma 28.11.2008

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

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

Is the doctor’s view a reliable measure of patients HRQOL?

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)

Anxiety

Pain

Lower sleep quality

Physical InactivityPoor PS

Cancer Related Fatigue

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

5FU/FA5FU/FA FFLFFL Garufi et al Anticancer Drugs ‘01Garufi et al Anticancer Drugs ‘01

CPT-11 + FF CPT-11 + FF 5-165-16

Garufi et al Cancer ‘01Garufi et al Cancer ‘01

EORTC 05011 EORTC 05011 CPT-11CPT-11 + FFL + FFL

5FU/FA5FU/FA Garufi et alGarufi et al

EJC ‘97EJC ‘97

Studi di Cronotherapia presso l’IREStudi di Cronotherapia presso l’IRE

CPT-11 CPT-11 bolus + FFL cronobolus + FFL crono Garufi et al BJC ‘03Garufi et al BJC ‘03

CPT-11 crono vs CPT-11 crono vs standard + FF standard + FF 4-104-10

Garufi et al EJC ’06 Garufi et al EJC ’06

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

Qol parameters

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

MULTIVARIATE

Performance Status 0.387 0.221-0.677 <0.0001

Global QoL 0.977 0.969-0.986 <0.0001

Analisi Univariata e Multivariata sec Cox per la Sopravvivenza

Individual patient circadian rhythmassessment by actigraphy.

Cortisol Ratio (Slope)

Serum TGF-

Serum IL-6

Symptoms

Robust Rhythm *(autocorrelation >0.47)

1.72(Steep)

Low Low Less fatigue, appetite loss.

Dampened Rhythm(autocorrelation <0.35)

1.60(Flat)

High High More fatigue and appetite loss.

* p = < 0.05

Correlation: Rest/activity and Cortisol rhythms,TGF- and cytokines, and symptoms.

Clin Cancer Res 2005; 11(5):1757-1764

Study Population Study timing Variable Methods Findings

Ancoli-Israel 2006

n=85 (34-79y)

Stage I-IIIPrior ChT Fatigue

Obj/Subj sleep quality

Circadian rhythm

MFSI, PSQI Actigraph

Significant correlation (p>.0001) between subjective measure of sleep

and fatigue

Andrykowski 1998

n=88 (35-76y)

Stage I-IIIAAfter ChT Fatigue

Sleep quality

CFS, PFS, PSQI Significant correlation between fatigue and sleep quality

Berger

1998

n=72 (33-69y)

Stage I/IIDuring 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/IIDuring 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/IIDuring/ 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 0-III

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-IIIAfter 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

• 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

Possible correlation between depression and fatigue Supp Care Cancer 2006, 12: 201-9

• 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

Change in the actigraphy measures over time were significantly correlated with chenges in fatigue, mood, and depression

Supp Care Cancer 2002, 10: 329-336

Circadian rhythm

Fatigue

Depression

Mood

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