Click to add text 9/12/12 TROUBLES EMOTIONNELS ET CANCER DE L OVAIRE CHEZ LA FEMME AGEE : UN CONCEPT «BIO-PSYCHO-CLINIQUE»?

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1 TROUBLES EMOTIONNELS ET CANCER DE L OVAIRE CHEZ LA FEMME AGEE : UN CONCEPT «BIO-PSYCHO-CLINIQUE»? G. Freyer, MD, Phd, GINECO Pdt Service d Oncologie Médicale CH Lyon-Sud, HCL, Université Lyon 1 Hall et al Cancer May 15;97(10 Suppl): Click to add text Hutchins et al. N Engl J Med Dec 30;341(27): Underrepresentation of patients 65 years of age or older in cancer- treatment trials. «Standard surgery»: 55 % «Optimal surgery» in AOC (III IV) No residuals : 45 % (< 10 mm : 62 %) Med McLean OS : 47.2 K.A. mo et al, Gynecologic Oncology 2010 Fotopoulou C. et al, Int J Gynecol Cancer 2010, 20: < 10 mm residuals (GINECO studies) : 21 % - Med OS : 23 mo Comorbidities, autonomy, Freyer G. et al, Ann Oncol 2005, 16: nutritional status = frailty = 41 % - Med OS : 25 mo geriatric oncology? Chan et al. Tredan O, Freyer G. et al, Ann Oncol 2007, 18: Br J Cancer Nov 20;95(10): Ovarian cancer in younger vs older women: a population-based analysis. 1

2 Elderly Patient Frailty Life Expectancy Geriatric Assessment Tumor Extent (adj / meta) Prognosis (tumor/ geriatric) Prospectives Studies Drug Variability (Inter/Intra I.) Therapeutic Index PK/PD Studies LA CHIMIOTHERAPIE Tendance générale au sous-traitement Sous-représentation dans les essais cliniques Aucune prise en compte des covariables gériatriques Pas de traitement standard après 70 ans («Mais CarboTaxol, ça passe très bien») Etudes rétrospectives ou de phase II (platine, taxane) très «rassurantes» Discordance avec la pratique clinique Rôle de l évaluation gériatrique? LE PROGRAMME FAG DU GINECO Evaluer la faisabilité des chimiothérapies «standard» après 70 ans, stades III-IV Identifier les paramètres gériatriques d intérêt Préciser le rôle du paclitaxel Pour cela : critères d éligibilité aussi larges que possible (> 70 ans, PS indifférent, chirurgie initiale ou non) 2

3 LE PROGRAMME FAG DU GINECO Essai FAG-1, patientes, 30 centres carboplatine AUC 5 + cyclophosphamide 600 mg/m², J1 J28, 6 cycles Essai FAG-2, patientes, 30 centres carboplatine AUC 5 + paclitaxel 175 mg/m², J1 J22, 6 cycles FAG 1 : faisabilité d une bithérapie par CC (carboplatine cyclophosphamide) Freyer G et al. Ann Oncol 2005, 16: FAG 2 : Faisabilité d une bithérapie par CP (carboplatine paclitaxel) , 75 patientes, 23 centres Objectif principal : faisabilité CP : 50 / 72 (68,5 % [61 76]) 3

4 PATIENTES FAG-1 FAG-2 Age médian 76 [70 90] 75 [70 89] PS 0-1 / 2-3 (%) 56 / / 26 [p = 0.08] Chirurgie optimale (%) [p = 0.03] Carcinome séreux (%) Stade III / IV (%) 76 / / 22 Ascite (%) médicaments / j [p = 0.03] FAISABILITE BENEFICE CLINIQUE Carboplatine cyclophosphamide 60 / 83 (72 % [65 80]) Carboplatine paclitaxel 50 / 72 (68.5 % [61-76]) Différence non significative Mais... FAG 2 : Patientes à co-variables plutôt plus favorables : PS (ns), qualité de la cytoréduction (41% contre 21%) Evaluation gériatrique moins perturbée En analyse multivariée : Stade IV : HR=3,05 ; p=0,001 Ttt / paclitaxel : HR=2,42 ; p=0,01 Dépression : HR=5,11 ; p<0,001 Lymphopénie : HR=4,68 ; p=0,006 Mais le PS est non significatif De plus, la lymphopénie est la seule co-variable associée en analyse multivariée à la dépression 4

5 SCORE HADS ET SURVIE GLOBALE Seuil discriminant = 15 (p = 0.01) Donc... Lymphopénie <0,5G/L p<0,05 Dépression p =0,006 p = 0,0001 p =0,006 (FAG 1 seulement) Survie Toxicités AGE, PSYCHOLOGIE ET CANCER : L HYPOTHESE TELOMERIQUE 5

6 Télomères et sénescence => Le télomère : témoin et acteur de la sénescence Télomères, âge et lymphocytes Cas particulier des lymphocytes B et T : activation transitoire de la télomérase en réponse à la stimulation antigénique Rôle de l âge : Age Erosion télomérique Activité télomérase? Dysfonction lymphocytaire Télomères, âge, lymphocytes et... dépression Autres facteurs de vulnérabilité? Dépression (désordres émotionnels) Grand Age Proc Natl Acad Sci USA, (49): FAG 1 taille des télomères Activité et ( = Erosion télomérique) télomérase FAG 2? Lancet, 2003;361(9355):393-5 Dysfonction lymphocytaire Survie (par réserve fonctionnelle) Lymphopénie 6

7 Development of a geriatric vulnerability score (GVS) in elderly advanced ovarian cancer (AOC) patients (pts) treated in first line: a prospective GINECO trial. ETUDE FAG 3 PROTOCOL PLAN Inclusion <10 days post inclusion Carboplatin AUC5 Geriatric assessment : CT-scan Comorbidities CA125 Comedications Function : ADL, IADL Nutrition Psycho-cognitive : MMSE, Mood & Distress thermometers GDS30 Psychologic assessment : Semi-directed DSMIV CT-scan CA125 CT-scan CA15-3 Evaluation of response Impact of emotional disorders on patients outcomes : See abstract «XXXX» (ASCO 2012) Rhondali et al. Impact of telomere length on patients outcomes : See abstract «XXXX» (ASCO 2012) Falandry et al. Impact of patient covariates on patient s survival Oncologic covariates FIGO stage IV Performance status > 2 Optimal cytoreduction Geriatric covariates Age > 80 Functional assessment : - ADL score < 6 - IADL score < 25 > 3 comorbidities Nutritional assessment : - Albuminemia < 35 g/l - Albuminemia < 30 g/l - BMI < 21 kg/m² - BMI < 19 kg/m² Lymphocytes < 1G/L Psychogeriatric assessment - Emotional disorders - HADS score > 14 - Mood thermometer > 4 Univariate HR p <

8 Development of a Geriatric Vulnerability Score (GVS) in multivariate analysis GVS = Σ vulnerability factors : Major : - score ADL < 6 - score IADL < 25 - albuminemia < 35g/L Minor : - Lymphopenia < 1G/L - score HADS > 14 OS (%) => Vulnerable if GVS 3 See poster 9079 by Freyer, G. et al.: Patient and survivor care Sat June 2: 8:00-12:00 GVS<3 GVS>3 Censored Time (months) Correlations between depression according DSM- IV-TR (DSM) criteria, three validated scales, oncologist assessment and clinical psychiatric interview in elderly advanced ovarian cancer (AOC) patients (pts) - a GINECO study METHODS Study design : multicenter open prospective trial Study end-points : this analysis was a secondary endpoint of the Elderly Women AOC trial, designed to assess the impact of geriatric covariates, notably depression, on survival in patients over 70 receiving 6 courses of carboplatin. Depression assessments : Geriatric Depression Scale-30 (GDS; cut off score of 10/30) Hospital Anxiety Depression Scale (HADS; cut off score of 15/42), Distress Thermometer (DT; cut off score of 4/10) Oncologist assessment (OA; yes/no). Clinical psychiatric interview (CPI; yes/no; by psychologists within 10 days after inclusion) DSM IV criteria (yes/no) as the gold standard 8

9 RESULTS Correlation between DSM IV and the different assessments Variables No Depression Depression Correla5on N= 84 N= 16 r ; p GDS [median (Q1- Q3)] HADS [median (Q1- Q3)] DT [median (Q1- Q3)] CPI N (%) OA N (%) 7 (5-12) 11 (7-17) r=0.58; p< (9-16) 15 (11-21) r=0.127;p= ( ) 4.5 ( ) r=- 0.07;p= (26) 14 (88) r=0.53; p< (18) 2 (13) r=- 0.05;p=0.733 DSM No depression Depression No depression- censored Depression Censored DSM Means and Medians for Survival Time Meana 95% Confidence Interval Median 95% Confidence Interval Estimate Std. Error Lower Bound Upper Bound Estimate Std. Error Lower Bound Upper Bound No depression Depression Overall CONCLUSIONS Depression was not a frequent finding in this populaqon with a lower frequency that what have been previously reported in the literarure (16% vs 45%) PaQents were not correctly idenqfied by oncologists with 87% of false negaqves and 18% of false posiqves whereas they were more frequently idenqfied by the CPI conducted by psychologists with 12% of false negaqves and 26% of false posiqves Lower overall survival for the group risk factor for cancer- related mortality but not staqsqcally significant The best sensiqvity and specificity as a screening tool was found for GDS, 94% and 80% respecqvely. The use of validated tools such as GDS and a collaboration between psychologists and oncologists are warranted to better identify emotional disorders in elderly women with AOC. 9

10 Les 3 essais vont dans le même sens (test d hétérogénéité non significatif) avec un HR global significatif à 1,67 pour les patients ayant un HADS >14 versus <14. HADS n ayant pas été recueilli dans Fag1 seuls les essais Fag2 et Fag3 ont été utilisés pour faire l analyse A weak correlation between telomere length and age 111 patients sampled, 109/111 evaluable (duplicate analysis) Telomere length Age Patient telomere length and treatment completion rate (TCr) With a cut-off of 5770bp, TL discriminates 2 groups of patients with different TCr Treatment completion rate (TCr) Telomere length 59% Short n = 34 80% Long n = 75 p=

11 Severe toxicity increases with telomere shortening event Observed Risk: short/ long telomere group 95% confidence interval Serious Adverse Events Unplanned hospital admissions Grade > 3 non-hematological toxicities P Vulnerability increases with telomere shortening No significant correlation with any of the GVS components BUT a correlation between patient telomere length (Short vs Long) and vulnerability (GVS 3; 2 major criteria) GVS = Σ vulnerability factors : Major : - score ADL < 6 - score IADL < 25 - albuminemia < 35g/L Minor : => Vulnerable if GVS 3 - Lymphopenia < 1G/L - score HADS > 14 Vulnerable pts (GVS > 3; > 2 major C, %) Telomere length Short OR = 2.17, p=0.06 Long Overall survival Overall survival Stage III, telomere size 6000bp Stage III, telomere size < 6000bp Stage IV, telomere size 6000bp Stage IV, telomere size < 6000bp Time (months) Multivariate analysis : Stage (IV vs III) HR=2,53 [ ]; p=0,0003 Telomere < 6000bp HR=1,57 [ ]; p=0,06 11

12 Back to the telomeric working hypothesis A partial overlap between TL and geriatric vulnerability factors Depression Emotional disorders Elderly woman GINECO trials 1 & 2 Survival Toxicities Other vulnerability factors? telomere length ( = telomere attrition) Old age? Lymphocyte dysfunction Lymphopenia telomerase activity 12