Terapia adiuvante nelle pazienti anziane. Esiste uno standard? Laura Biganzoli Oncologia Medica Istituto Toscano Tumori Prato

Senior adults: heterogeneity in health status The simplest way to explain the marked heterogeneity of this population is by presenting you this data on life expectancy …. CGA, comprehensive geriatric assessment

Drug-drug interactions The iceberg of aging Comorbidities Performance status Chronological age Medications Functional status Cognition Geriatric syndromes Socio-economic status Polypharmacy/ Drug-drug interactions Nutrition

Adjuvant therapy: which and to whom ? TARGET the TUMOR TARGET the PATIENT Stage Biology Physiological age Estimated life expectancy Treatment tolerance Patient preference Potential barriers to treatment La pianificazione del trattamento adiuvante nella paziente anziana ha sicuramente un livello superiore di complessita’ rispetto alla paziente piu’ giovane legato all’eterogenicita’ dell’invecchiamento. La decisione non puo’ prescindere dalle caratteristiche del tumore, intese come MA FONDAMENTALE E’ UN ACCURATA VALUTAZIONE DELLE CONDIZIONI GENERALI Potential risks vs. expected absolute benefits

Endocrine therapy Hershman et al. Brest Cancer Res Treat 2011 Chirgwin et al. J Clin Oncol 2016 Compliance should be actively promoted 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

Potential barriers to oral therapy adherence in older patients Factor Barriers Age-related 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 AC/CMF vs capecitabine (X) 633 women aged ≥65 stage I-IIIB BC AC/CMF vs capecitabine (X) OS disadvantage with X ELDA trial 302 women aged 65-79 average-high risk of relapse CMF vs weekly docetaxel(D) Weekly D worsens QoL & toxicity deintensificazione 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 Taxanes can replace anthracyclines to reduce the cardiac risk 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 Jones et al. J Clin Oncol 2009 TC > AC as in younger patients. More febrile neutropenia Biganzoli et al. Lancet Oncol 2012

Intensive regimens ie. AT 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 Questi numeri non si possono spiegare con la sola presenza di comorbidita’ o rifiuto; verosimilemnte 2 fattori maggiori sono legati al fatto che trastuzumab implica chemio e paura tossicita’ di trastuzumab e sua associazione con chemio sul cuore Reeder-Hayes et al. J Clin Oncol 2016

Potential concerns Under-representation in clinical trials Risk of cardiac toxicity Age distribution in trastuzumab adjuvant trials Trial Median age Pts ≥60 yrs HERA 49 16% NSABP-B31/ NCCTG-N9831 NA 18% FinHER 50 BCIRG 006 <50% age >50 yrs Potential risk factors for CHF/cardiac events NSABP B31 NCTG N9831 HERA ACREC Age 50+ Hypertension medic. Baseline LVEF (<55%) Post-AC LVEF Age 60+ Hypertension medic. Baseline LVEF (<55%) Baseline LVEF (<65%) High BMI (>25) Age >50 Post-AC LVEF Romond et al. JCO 2012; Perez et al. JCO 2008; Sutter et al. St Gallen 2007; Russel et al. JCO 2010

Pooled proportion of cardiac events = 5% * * Pts >60 years Pooled proportion of cardiac events = 5% ………….The use of trastuzumab should be considered as a standard of care in the adjuvant therapy of elderly patients with HER-2 positive breast cancer……… 47% relative risk reduction 2012

T-related cardiac toxicity in the real word

2,203 (23.1%) received trastuzumab 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 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 CHF-free survival for pts with BC, time since BC diagnosis to first CHF claim according to trastuzumab use. 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 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 Terapia adiuvante nelle pazienti anziane. Esiste uno standard? CONCLUSIONS Unfit patients Standard=evidence-based Standard=reasonable options

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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 CRASH Score Hematologic (H) risk factors Diastolic BP (≥72mmHg = 1) IADL (<26 = 1) LDH (>459 = 2) Non-hematological risk (NH) factors ECOG PS (1-2 = 1; 3-4 = 2) MMS (<30 = 2) MNA (<28 = 2) Chemotherapy risk (according to MAX2 Scores) H score (including chemo risk) NH score (including chemo risk) Combined score (count chemo risk once) CARG Score Score Age ≥72 years 2 Cancer type GI or GU Standard CT dose Polychemotherapy (>1 CT drug) Hemoglobin <11 g/dL (males); <10 g/dL (females) 3 Creatinine clearance <34 mL/min Hearing impairment Functional impairment Any falls in last 6 months IADL: some help/unable to take medications Walking 1 block (somewhat) limited Decreased social activity 1 Total 23 H score NH score Combine Risk 0-1 0-2 0-3 low 2-3 3-4 4-6 Low-medium 4-5 5-6 7-9 Medium-high >5 >6 >9 high SCORE RISK 1-5 low 6-9 medium ≥10 high