Terapia adiuvante nelle pazienti anziane. Esiste uno standard?

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

2. Senior adults: heterogeneity in health status CGA, comprehensive geriatric assessment

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

4. 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 Potential risks vs. expected absolute benefits

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

6. Potential barriers to oral therapy adherence in older patients 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.

7. Chemotherapy CALGB 49907 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 Muss et al. N Engl J Med 2009 Perrone et al. Ann Oncol 2015 Elderly fit patients should be treated with standard regimens

8. Which regimens should be used in fit pts? • CALGB 49907 (CMF vs AC) - ↑ G3-4 NH toxicity vs AC (40% vs 24%) - Reduced compliance • 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 Muss et al. N Engl J Med 2009 • TC > AC as in younger patients. More febrile neutropenia Jones et al. J ClinOncol 2009 Four cycles of an anthracycline-containing regimen are usually preferred over CMF Taxanes can replace anthracyclines to reduce the cardiac risk Biganzoli et al. Lancet Oncol 2012

9. Intensive regimens ie. AT in high-risk healthy elderly patients Biganzoli et al. Lancet Oncol 2012

10. 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 ClinOncol 2014 Weekly paclitaxel may be considered in high-risk pts who are not candidates for poly-chemotherapy Biganzoli et al. Cancer Treat Rev 2016

11. Adjuvant trastuzumb Reeder-Hayes et al. J Clin Oncol 2016

12. Potential concerns Age distribution in trastuzumab adjuvant trials • Under-representation in clinical trials • Risk of cardiac toxicity Romond et al. JCO 2012; Perez et al. JCO 2008; Sutter et al. St Gallen 2007; Russel et al. JCO 2010

13. Pooled proportion of cardiac events = 5% * * Pts >60 years ………….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

14. T-related cardiac toxicity in the real word

15. 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

16. 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

17. 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

18. Terapia adiuvante nelle pazienti anziane. Esiste uno standard? CONCLUSIONS • Unfit patients • Standard=evidence-based • Standard=reasonable options

19. Back up

20. NCCN Guidelines – Senior Adult Oncology

21. How can we precisely define a fit patient?

22. 34 • 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 Geriatric assessment CGA cannot be used to select patients for adjuvant chemotherapy Biganzoli et al. Lancet Oncol 2012

23. Predicting chemotoxicity