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

2. 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

3. 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

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
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

5. 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

6. 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.

7. 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 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

8. Which regimens should be used in fit pts?
CALGB (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

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 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

11. 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

12. 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 Hypertension medic. Baseline LVEF (<55%) Post-AC LVEF
Age Hypertension medic Baseline LVEF (<55%)
Baseline LVEF (<65%) High BMI (>25)
Age > Post-AC LVEF
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
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

14. T-related cardiac toxicity in the real word

15. 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

16. N = 18,540 Median age, 54 years; interquartile range, 47 to 63 years N=3891 ≥65 yearsB
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] 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
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
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

23. 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