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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. 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
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