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Particularités des cancers du sujet agé Docteur Etienne Brain Oncologie Médicale HÔPITAL RENÉ HUGUENIN Au 1er janvier 2010, le Centre René Huguenin devient l’Hôpital René Huguenin, un établissement de soins, d’enseignement et de recherche de l’Institut Curie Projected number of cancer cases for 2000–2050 by age group (<45, 45–64, 65–84, 85+) based on projected census population estimates and delay-adjusted SEER-17 cancer incidence rates. Hayat M J et al. The Oncologist 2007;12:20-37 ©2007 by AlphaMed Press Incidence du cancer de 2010 à 2030 (Smith JCO 2009) • +11% < 65A • +67% > 65A Les plus fréquents chez le sujet âgé Cancer Statistics in the USA 2008, CA Cancer J Clin 2008 Pourquoi cette question ? 1. Les sujets âgés peuvent bénéficier des traitements 2. Le nihilisme thérapeutique : les sujets âgés ne reçoivent pas de traitement 3. L’enthousiasme thérapeutique aveugle : les sujets âgés reçoivent un traitement « futile » 4. Places du gériatre et de l’oncologue Definition of “old” x ageing heterogeneity Men life expectancy Top 25th% 50th% Lowest 25th% Fit Intermediate Sick 50 36 28.5 19.6 70 18 12.4 6.7 75 14.2 9.3 4.9 80 10.8 6.7 3.3 85 7.9 4.7 2.2 90 5.8 3.2 1.5 95 4.3 2.3 1 Age Walter. JAMA 2001 Comorbidity across age dementia CHF solid tumour AIDS diabetes hypertension Piccirillo. Critical Rev Oncol Haematol 2008 3-year mortality rates by level of comorbidity for women w/ BC Cause of death No. of co-morbidity None 1 2 3+ All BC Other 47.7 34.0 8.3 68.6 41.0 (0.04) (>0.2) 108.3 47.4 (<0.001) (>0.2) 188.4 40.3 (<0.001) (>0.2) 24.3 (0.01) 56.2 (<0.001) 162.6 (<0.001) Ratio of BC to other causes of death 4.1 1.7 0.8 0.3 Satariano & Ragland 1994 Confronting Alzheimer’s disease!! Okie, NEJM 2011 Heterogeneity is multifactorial 1. Elderly – 75 yo vs 90 yo – No comorbidity vs dementia 2. Cancers – Kidney cancer – M+ colorectal cancer – High grade NHL curative surgery surgery + chemotherapy intensive chemotherapy 3. An early stage breast tumour – ER– ER+ surgery + XRT + chemotherapy surgery + XRT + endocrine treatment ± chemotherapy Représentativité & études • SWOG – 164 études (1993-1996) – 16000 sujets • FDA – 55 études AMM – 29000 sujets 35% de tous les cancers > 75A = 10% des inclusions > 65A Hutchins NEJM 1999 ; Talarico JCO 2004 Modifications physiologiques - PK & PD Mécanisme Absorption Conséquences Vidange et secrétions gastriques : Hépatocytes, circulation, Métabolisme activité CYP P450 : Interactions (CYP P450) Absorption de protéines, vitamines et drogues : Synthèse protéique, activation/désactivation des drogues et carcinogènes : Vd drogues hydrosolubles : Vd drogues liposolubles : Distribution H2O, albumine, Hb : Excrétion Elimination des drogues GFR, filtration tubulaire : excrétées par le rein : Excrétion biliaire : Elimination biliaire : Balducci Oncologist 2000, Wildiers Clin Pharmacokinet 2003 Adjuvant chemo for breast cancer DFS ≤50 All • CALGB (1975-1999) • 4 randomized trials • 6487 pts > 65 yo > 70 yo ≥65 51-64 OS 542 (8%) 159 (2%) All ≤50 51-64 ≥65 • Results – Benefit – Toxicity identical careful!! • Toxic deaths 1.5% Muss. JAMA 2005 CBNPC Stade III-IV 70-89 ans PS 0-2 Carboplatine AUC 6 J1 Paclitaxel 90 mg/m2 J1, J8, J15 J1 = J29, 4 Cy R 1:1 Vinorelbine* 30 mg/m2 J1, J8 ou Gemcitabine* 1.150 mg/m2 J1, J8 J1 = J22, 5 Cy • • Stratification : centre, PS 0-1 vs 2, ≤ 80 vs > 80 ans, stade III vs IV • • Objectifs secondaires : PFS, RR, toxicité de grade 3-4 Erlotinib** 150 mg/J *Choix par chaque centre **Si progression ou toxicité Objectif principal : OS Statistiques : OS1A 30% vs 40%, α 5% β 20%, 520 patients, 2 analyses intermédiaires Pas de GCSF en prophylaxie primaire Median OS 10.3 mth [8.3-12.6] vs 6.2 mth [5.3-7.3] Median PFS 6.0 mth [5.5-6.8] vs 2.8 mth [2.6-3.7] Targeted treatments Clinical evidence for benefit But « short » of specific data! ATE and bevacizumab Chemo only Chemo + beva N = 782 N = 963 Global 1.7 3.8 No risk factor 1.0 1.8 < 65 yo 1.4 2.1 65 yo (N = 279) Previous history of ATE 2.5 3.4 7.1 15.7 65 yo and previous history 2.2 17.9 ATE events Scappaticci. J Natl Cancer Inst 2007 Signatures ? Oncotype DX® et TAILORx Phénomène hétérogène Problème démographique ? Mortalité spécifique et effets secondaires significatifs Espérance de vie ou pronostic « hors cancer » Recherche clinique peu représentée The tools? Comprehensive Geriatric Assessment Paramètres Outils Impact Autonomie PS, Activity of Daily Living Scale (ADL), Instrumental Activity of Daily Living Scale (IADL) Espérance de vie, dépendance, stress Comorbidités Nombre, sévérité (Index de comorbidités) Espérance de vie, stress (pronostic ?) Socio-économique Conditions de vie, aidants, soignants Cognition Folstein Mini-mental status (MMS) Espérance de vie, dépendance Emotion Echelle de dépression gériatrique (GDS) Survie (motivation au traitement ?) Médicaments N, indications, interactions Interactions Nutrition Mini Nutritional Assessment Scale (MNA) Réversible (survie ?) Syndromes gériatriques Démence, délire, chutes Survie, dépendance Balducci Oncology 2006 Impact de l’EGA sur traitement ? • Etude ELCAPA 01 – 375 patients 70+ avec EGA • Age 79.6±5.6 • 53% femmes, 59% tumeurs digestives • N comorbidités 4.2±2.7, CIRSG 11.8±5.3 – Modification de la décision thérapeutique initiale > EGA • 21% (95%CI 16.8-25.3) dont 81% diminution • Analyse unifactorielle – – – – – – PS ≥ 2 ADL Malnutrition Troubles cognitifs Dépression Comorbidités 73% vs 41% 59% vs 24% 82% vs 51% 39% vs 25% 53% vs 22% 4.8±2.9 vs 4.0±2.6 • Analyse multifactorielle ADL et malnutrition Caillet J Clin Oncol 2011 Ability of (A) risk score versus (B) physician-rated Karnofsky performance status (KPS) to predict chemotherapy toxicity. Hurria A et al. JCO 2011;29:3457-3465 ©2011 by American Society of Clinical Oncology Bilan groupe GERICO Age Phase Critère principal de jugement N 2002 Création (F Pein et AC Braud) G-01 : CT orale (X+VNR) sein, poumon, prostate M+ G-02 : CT XELOX CCR M+ 70+ 70+ II II ADL ADL 80 60 2004 G-03 : RT interstitielle per opératoire sein < 3 cm N- 70+ II Qualité 40 2005 G-04 : CT TxT biweekly sein M+ G-05 : CT TxT biweekly NSCLC M+ 70+ 70+ II II IADL IADL 27/58 5/58 2006 G-06 : CT adjuvante anthracyclines (MC) sein RH- 70+ II ADL 40 2008 G-07 : validation CRASH Étude sarcome Aegide + GSF 70+ 70+ Cohorte II R Composite Composite NA NA 2009 G-09 : sein M+ HER2+++ X + lapatinib Rétrospective L1 CT M+ sein (Bergonié) DOGMES L1 CT DXR liposomale (ARCAGY) 70+ 75+ 70+ II Cohorte II Composite Descriptif RR 52 > 500 60 2010 G-10/GETUG P-03 : CT TxT prostate + PK PRODIGE 20 (G-08) : CT ± bevacizumab CCR M+ 75+ 75+ II R II R / III Composite Composite 72-128 116 2011 G-11/PACS 10 : CT adjuvante sein RH+, espérance de vie et score pronostique 70+ III OS 700 (1200) CGA and cancer • No evidence on how to use CGA in individual specific cancer patients for making treatment decisions • Strong evidence in the general population that CGA-directed intervention improves survival & QoL • Some evidence in the general cancer population that CGA can contribute to the management of patients – There are some geriatric domains (cognition, nutrition, co-morbidities, depression, functionality) that if assessed & managed could result in improved compliance, improved tolerability of therapy and increased survival Increase research Move from a prejudice-based to an evidence-based medicine CGA: 1 for all or all for 1? • For whom? – – – – Curative vs palliative Adjuvant vs metastatic Agressive vs chronic Etc. • Screening tool? Screening pour oncodage… …ou "screenage" pour onco dingues ! G8 • G1 = “fit” – Aucune anomalie – CIRSG • grade ≤ 2 – (I)ADL normal – MNA normal – Ttt standard • G2 “vulnérable” (réversible) – CIRSG • ≥ 1 de grade 3 – ≥ 1 volet IADL – Risque de dénutrition • 17 ≤ MNA < 24 – Ttt standard ± intervention gériatrique • G3 “fragile” (non réversible) – CIRSG • ≥ 2 de grade 3 ou • ≥ 1 de grade 4 – ≥ 1 volet ADL – Dénutrition sévère • MNA < 17 – Altération cognitive • 15 < MMSE 24 – DTS, confusion répétées – Ttt symptomatique ± actions spécifiques • G4 – – – – Dépendance, démence Comorbidités majeures Grabataire, terminal Ttt palliatif Recommendations for elderly cancer patients • • Special attention to – Evaluation of CrCl (Cockroft and MDRD) mandatory – Cognitive status, depression, anxiety, social settings: can influence patient decisions – Multiple medications (+ OTC and alternative medicines): frequent, drug-drug interactions+++ – High risk of poor compliance (living alone or with cognitive impairment) AEs – Underestimation of true prevalence – Close monitoring to allow prompt intervention – Atypical presentations – Concomitant medications – Use of G-CSF and ESA Expectations may vary considerably in terms of disease outcomes, benefits from therapy and must be considered in joint decision making Competing causes of mortality Prostate Breast NHL Cumulative probability of death Cumulative probability of death vs attained age Competing HR of death Deaths attributed to the primary cancer (solid dots) and those attributed to comorbidity (open circles) Kendal. Cancer 2008 4-year mortality score in general elderly population Health retirement study • > 50 yo (40% > 70 yo) − Construction 11,701 subjects − Validation Score ≥ 8 = 25% of 70+ Score ≥ 8 = 50% of 75+ 8,009 subjects Lee. JAMA 2006 CGA Microarray qRT-PCR Protocol ASTER 70s GERICO 11 / PACS10 AAdjuvant systemic treatment for oestrogen-receptor (ER)-positive HER2-negative breast carcinoma in women over 70 according to Genomic Grade (GG): chemotherapy + endocrine treatment versus endocrine treatment. A French UNICANCER Geriatric Oncology Group (GERICO) and Breast Group (UCBG) multicentre phase III trial ASTER 70s - Design Arm A = HT** informed consent EBC ≥70 yo Surgery ER+ HER2Lee’s score§ G8 score § 4-yr mortality rate Group I high GG pN (pN0 vs pN+) G8 (≤ vs > 14) Centre by RT-PCR Arm B = CT + HT** Group II low GG by RT-PCR HT CT ** hormonotherapy 5 years 4 cycles (TC, AC or MC) + GCSF ± XRT according to standard guidelines NO CHEMOTHERAPY IS RECOMMENDED Follow up + inclusions in other studies (e.g ELD15 validation) - Low GG - Other causes for non inclusion (refusal, geriatrics, etc.) Patients will be offered HT according to standard guidelines 700 pts (+ 1100-1300 not included i.e. low GG or other causes followed up) 1/ 4-yr OS 2/ Tolerance, DFS, QoL (ELD15), Q-TWiST, G8, cost-effectiveness analysis, GG/RT-PCR, TR, geriatrics Phase III w/ 4-yr OS Hypothesis B > A 7.5% (A 80% vs B 87.5%) HR 0.60 Inclusion period 4 years 170/year Follow up 4 years 129 events 5% 20% 340 pts/arm FEC, AACR, FAC, ASCO, CMF, DXR, PK/PD, CEX, 5FU CDDP, RPC, AUC Calvert, ESMO, AUC Chatelut, PK pop, FOLFIRI, FOLFOX 7, CPA, DFS, GERCOR, SOMPS, OS, TTP, NCI, CYP P450, JCO, JNCI, EJC…etc. ADL, Charlson, CIRSG, EGS, EGA, MNA, GDS, MMS, ADL, IADL, GFI, CMR2, JAGS…etc. FEC, FAC, ADL, IADL, CMF, DXR, PK/PD, CEX, 5FU CDDP, AUC Calvert, GDS, AUC Chatelut, PKpop, FOLFIRI, MMS, FOLFOX, CPA, DFS, OS, TTP, NCI, EPOG, GERICO, TFE, JCO, JNCI, Charlson, CIRSG, EGS, EGA, MNA, GFI, JAGS, JOG, JGO…etc. Multidisciplinarité en 2006 ? Freyer Ann Oncol 2006 En 2012 ?? 40% 20% ?? Il n'y a rien de plus ridicule qu'un oncologue qui ne meurt pas de vieillesse François Marie Arouet (1694-1778)
