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Terapia adiuvante nelle pazienti anziane. Esiste uno standard? Laura Biganzoli Oncologia Medica Istituto Toscano Tumori Prato Senior adults: heterogeneity in health status CGA, comprehensive geriatric assessment The iceberg of aging Comorbidities Chronological age Performance status Medications Functional status Cognition Geriatric syndromes Socio-economic status Nutrition Polypharmacy/ Drug-drug interactions Adjuvant therapy: which and to whom ? TARGET the TUMOR - Stage - Biology TARGET the PATIENT - Physiological age - Estimated life expectancy - Treatment tolerance - Patient preference - Potential barriers to treatment Potential risks vs. expected absolute benefits Endocrine therapy • As for younger postmenopausal pts; however, elderly patients are more vulnerable to toxicity and safety is important in choice of agent • Omission is an option for patients with a very low-risk tumour (pT1aN0) or life-threatening comorbidities • Compliance should be actively promoted Biganzoli et al. Lancet Oncol 2012 Hershman et al. Brest Cancer Res Treat 2011 Chirgwin et al. J Clin Oncol 2016 Potential barriers to oral therapy adherence in older patients Factor Age-related Barriers • • • • • • • • Cognitive deficits Visual/hearing impairment Comorbidities ± geriatric syndromes Disease severity and associated symptoms Higher risk of toxicity Polypharmacy Regimen complexity Personal health beliefs, including perceived need & effectiveness of treatment • Low health literacy • Poor socio-economic status or lack of social support or supervision • Poor physician-patient communication Adapted from: Sabate, E. Adherence to long-term therapies:Evidence for Action. World Health Organization, 2003. Kardas, P. et al. Frontiers in Pharm. 2013;4(91). Henriques M. et al. Journal of Clinical Nursing, 21, 3096–3105. Chemotherapy CALGB 49907 ELDA trial 633 women aged ≥65 stage I-IIIB BC AC/CMF vs capecitabine (X) 302 women aged 65-79 averagehigh risk of relapse CMF vs weekly docetaxel(D) • OS disadvantage with X • Weekly D worsens QoL & toxicity Muss et al. N Engl J Med 2009 Perrone et al. Ann Oncol 2015 Elderly fit patients should be treated with standard regimens Which regimens should be used in fit pts? • CALGB 49907 (CMF vs AC) - ↑ G3-4 NH toxicity vs AC (40% vs 24%) - Reduced compliance Muss et al. N Engl J Med 2009 Four cycles of an anthracycline-containing regimen are usually preferred over CMF • 10-yr Cardiac Failure Rate in women aged 66 to 70: Anthracycline-based adjuvant chemotherapy= 47%, CMF = 33%, no chemotherapy = 28% Giordano et al. ASCO 2006 • TC > AC as in younger patients. More febrile neutropenia Jones et al. J Clin Oncol 2009 Taxanes can replace anthracyclines to reduce the Biganzoli et al. Lancet Oncol 2012 cardiac risk Intensive regimens ie. AT in high-risk healthy elderly patients Biganzoli et al. Lancet Oncol 2012 Is there any role for adjuvant chemotherapy in unfit patients? CALGB 40101 Operable breast cancer with 0 to 3 positive nodes Single agent paclitaxel (P) vs AC • AC more toxic • The trial did not show noninferiority of P to AC 1% absolute difference in OS Shulman et al. J Clin Oncol 2014 Weekly paclitaxel may be considered in high-risk pts who are not candidates for poly-chemotherapy Biganzoli et al. Cancer Treat Rev 2016 Adjuvant trastuzumb Reeder-Hayes et al. J Clin Oncol 2016 Potential concerns • Under-representation in clinical trials Age distribution in trastuzumab adjuvant trials Trial Median age Pts ≥60 yrs HERA 49 16% NSABP-B31/ NCCTG-N9831 NA 18% FinHER 50 NA BCIRG 006 <50% age >50 yrs • Risk of cardiac toxicity Potential risk factors for CHF/cardiac events NSABP B31 NCTG N9831 Age 50+ Age 60+ Hypertension medic. Hypertension medic. Baseline LVEF (<55%) Baseline LVEF (<55%) Post-AC LVEF HERA Baseline LVEF (<65%) High BMI (>25) Romond et al. JCO 2012; Perez et al. JCO 2008; Sutter et al. St Gallen 2007; Russel et al. JCO 2010 ACREC Age >50 Post-AC LVEF * * Pts >60 years Pooled proportion of cardiac events = 5% 47% relative risk reduction ………….The use of trastuzumab should be considered as a standard of care in the adjuvant therapy of elderly patients with HER2 positive breast cancer……… 2012 T-related cardiac toxicity in the real word 9,535 BC patients at least 66 years old, diagnosed with stage I-III BC between 2005 and 2009, and treated with chemotherapy ( SEER- Medicare and in the Texas Cancer Registry–Medicardata bases) 2,203 (23.1%) received trastuzumab Median age entire coohort =71 years (>75 +/- 20%) CHF-free survival for pts with BC, time since BC diagnosis to first CHF claim according to trastuzumab use. • CHF rate 29.4% (T) vs 18.9% (noT) (P .001) • T users more likelyto develop CHF than noT users (HR1.95; 95% CI, 1.75 to 2.17) • older age (>80 years; HR1.53), coronary artery disease (HR 1.82), hypertension (HR 1.24), and weekly T administration (HR1.33) increased the risk of CHF Chavez-MacGregor et al. J Clin Oncol 2013 N = 18,540 Median age, 54 years; interquartile range, 47 to 63 years N=3891 ≥65 years A B Cumulative incidence of major cardiac events stratified by age (A <65 years ;B ≥ 65 years) compared with matched control population Thavendiranathan et al. J Clin Oncol 2016 Adjuvant trastuzumb: My point of view • Fit elderly patients should receive adjuvant chemotherapy plus trastuzumab1 • Consider A-free regimens if concern about cardiac toxicity ie. TC (docetaxel+cyclo) [0.4% G3 cardiac disfunction]2 Concern about use of TCH (docetaxel+carbo) in older patients. Weekly paclitaxel [0.5% symptomatic CHF] 3 if high risk tox from polychemotherapy or low risk of relapse (stage I). • Accurate evaluation cost/benefit in small tumors ie. pT1b • Consider T without chemo if contraindication to chemotherapy (CT) or CT-refusal in high risk patients 1Biganzoli et al. Lancet Oncol 2012; 2 Jones et al. Lancet Oncol 2013; 3Tolaney et al. N Engl J Med 2015 Terapia adiuvante nelle pazienti anziane. Esiste uno standard? CONCLUSIONS • Unfit patients • Standard=evidence-based • Standard=reasonable options Back up NCCN Guidelines – Senior Adult Oncology How can we precisely define a fit patient? 34 Geriatric assessment • General health and functional status for older individuals may be captured by collaborative geriatric and oncology management • Active intervention for comprehensive geriatric assessment (CGA)-identified reversible deficits in geriatric domains may reduce morbidity and mortality, and improve quality of life CGA cannot be used to select patients for adjuvant chemotherapy Biganzoli et al. Lancet Oncol 2012 Predicting chemotoxicity CARG Score CRASH Score Score Hematologic (H) risk factors Age ≥72 years 2 Diastolic BP (≥72mmHg = 1) Cancer type GI or GU 2 IADL (<26 = 1) Standard CT dose 2 LDH (>459 = 2) Polychemotherapy (>1 CT drug) 2 Non-hematological risk (NH) factors Hemoglobin <11 g/dL (males); <10 g/dL (females) 3 Creatinine clearance <34 mL/min 3 Hearing impairment 2 ECOG PS (1-2 = 1; 3-4 = 2) MMS (<30 = 2) MNA (<28 = 2) Functional impairment •Any falls in last 6 months •IADL: some help/unable to take medications •Walking 1 block (somewhat) limited •Decreased social activity Chemotherapy risk (according to MAX2 Scores) H score (including chemo risk) NH score (including chemo risk) Combined score (count chemo risk once) 3 1 2 1 Total 23 H score NH score Combine Risk 0-1 0-2 0-3 low SCORE RISK 2-3 3-4 4-6 Low-medium 1-5 low 4-5 5-6 7-9 Medium-high 6-9 medium >5 >6 >9 high ≥10 high