1. Dott. Carlo Garufi Oncologia Medica C Istituto Regina Elena, Roma Scuola Mediterranea di Oncologia “Actigrafia nel tumore della mammella” Roma 28.11.2008

2. 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

4. 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?

5. 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

6. (Cleeland, et al, 2004)

7. Anxiety Pain Lower sleep quality Physical Inactivity Poor PS Cancer Related Fatigue

11. 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.

12. 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

13. 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

14. 5FU/FA FFL Garufi et al Anticancer Drugs ‘01 CPT-11 + FF 5-16 Garufi et al Cancer ‘01 EORTC 05011 CPT-11  + FFL  5FU/FA  Garufi et al EJC ‘97 Studi di Cronotherapia presso l’IRE CPT-11 bolus + FFL crono Garufi et al BJC ‘03 CPT-11 crono vs standard + FF 4-10 Garufi et al EJC ’06

15. VariablesHazard ratio (HR)95% Confidence IntervalP-value UNIVARIATE Sex0.6770.462-0.9910.04 Performance Status0.2770.163-0.469<0.0001 Agen.s. Site of primary tumorn.s Number site involved0.6050.402-0.9110.01 Qol parameters Physical Functionig0.9880.979-0.9960.004 Emotional Functioning0.990.982-0.9980.01 Social Functioning0.9920.923-1.0000.04 Fatigue1.0141.007-1.021<0.0001 Pain1.0111.004-1.0180.002 Nausea/vomitingn.s. Appetite Loss1.0071.000-1.0140.04 Costipationn.s. Diarrhoean.s. Global QoL0.9780.970-0.986<0.0001 MULTIVARIATE Performance Status0.3870.221-0.677<0.0001 Global QoL0.9770.969-0.986<0.0001 Analisi Univariata e Multivariata sec Cox per la Sopravvivenza

16. Individual patient circadian rhythm assessment by actigraphy. Cortisol Ratio (Slope) Serum TGF-  Serum IL-6 Symptoms Robust Rhythm * (autocorrelation >0.47) 1.72 (Steep) Low Less fatigue, appetite loss. Dampened Rhythm (autocorrelation <0.35) 1.60 (Flat) 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

18. StudyPopulationStudy timingVariableMethodsFindings Ancoli-Israel 2006 n=85 (34-79y) Stage I-III Prior ChTFatigue 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-IIIA After ChTFatigue Sleep quality CFS, PFS, PSQISignificant correlation between fatigue and sleep quality Berger 1998 n=72 (33-69y) Stage I/II During ChTFatigue 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 ChTFatigue 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 ChTFatigue 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 ChTFatigue Sleep disturbance Energy fatigue subscale MOSSS Fatigue is strongly associated with sleep disturbance Broeckel 1998 n=61 (29-75y) After ChTFatigue 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 ChTFatigue 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 ChTFatigue Sleep problems MSASSleep 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 scaleInsufficient sleep is one of the determinat of fatigue Roscoe 2002 n=78 (34-79y) During ChtFatigue Circadian sleep rhythm FSC Actigraph Increased circadian rhythms disruption correlates with increased fatigue

20. 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

21. 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

22. Berger et al., J Pain Sympt Manag 2007

23. 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

24. Roscoe et al., Supp Care Cancer 2002

25. 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