Scuola Mediterranea di Oncologia Actigrafia nel tumore della

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 Ch. T for early stage BC • Higher fatigue levels are related to sleep maintenance problems and low daytime activity in pts after Ch. T • 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/va 0502/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 (Qo. L) 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 Qo. L and symptom scores as fatigue and anorexia was confirmed for the first time in a multicenter setting

Studi di Cronotherapia presso l’IRE 5 FU/FA Garufi et al EJC ‘ 97 5 FU/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 Qo. L 0. 978 0. 970 -0. 986 <0. 0001 Performance Status 0. 387 0. 221 -0. 677 <0. 0001 Global Qo. L 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 Less fatigue, appetite loss. 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 -79 y) Stage I-III Prior Ch. T Fatigue Obj/Subj sleep quality Circadian rhythm MFSI, PSQI Actigraph Andrykowski 1998 n=88 (35 -76 y) Stage I-IIIA After Ch. T Fatigue Sleep quality CFS, PSQI Berger 1998 n=72 (33 -69 y) Stage I/II During Ch. T Fatigue Activity and rest cycle PFS Actigraph Fatigue and disrupted activity/sleep inversely related (p<. 05) Berger 1999 n=72 (33 -69 y) Stage I/II During Ch. T 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 -69 y) Stage I/II During/ after Ch. T Fatigue Activity and rest cycle Actigraph, MSD, SES, PFS Low activity, disrupted sleep and increased distress werecorrelated with fatigue Bower 2000 n=1957 (mean 55 y) Stage 0 -III After Ch. T Fatigue Sleep disturbance Energy fatigue subscale MOSSS Fatigue is strongly associated with sleep disturbance Broeckel 1998 n=61 (29 -75 y) After Ch. T 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 -63 y) Stage 0 -III After Ch. T Fatigue Sleep duration Likert scale, diary sleep duration Fatigue after treatmento not correlates with sleep duration Jacobsen 1999 n=54 (28 -77 y) stage I-III During Ch. T Fatigue Sleep problems MSAS Sleep problems associated with significant increase in fatigue severity Okuyama 2000 n=134 (28 -86 y) Stage 0 -III After surg, Ch. T, RT Fatigue Sleep CFS, Likert scale Insufficient sleep is one of the determinat of fatigue Roscoe 2002 n=78 (34 -79 y) 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) Ch. T Ø Women report fatigue and disturbed sleep before Ch. T begins Ø Significant relationship between subjective poor sleep and fatigue and/or reduction of functional outcome Ø Objective measures confirm disrupted and disturbed sleep Ø However no significant correlation between objective sleep variable at night or during the day and fatigue and/or functional outcome ØAlthough their circadian rhythms are robust, pts with more delayed rhythms experience more daily disfunction secondary to fatigue Supp Care Cancer 2006, 12: 201 -9 Ø Possible correlation between depression and fatigue

• 219 women with stage I-IIIA breast cancer • Evaluation 48 h prior adjuvant Ch. T • 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