Mediterranean School of OncologyDirector :Prof.Stefano Iacobelli

Impact of Patient Age on Treatment of CRC

Advanced Course: Highlights in the Management of CRCRoma, 1-2 febbraio 2007

Domus Sessoriana

Prof.I.CarrecaChair of Medical Oncology,Chief

University of Palermo-Italy

Young old: 65-74 years of ageYoung old: 65-74 years of age

Older old: 75-84 years of ageOlder old: 75-84 years of age

Oldest old: over 85 years of ageOldest old: over 85 years of age

Elderly people………..?

0

500

1000

1500

2000

2500

3000

3500

4000

Uomini Donne

25-29aa

30-34aa

35-39aa

40-44aa

45-49aa

50-54aa

55-59aa

60-64aa

65-69aa

70-74aa

75-79aa

80-84aa

Frequenza per Frequenza per 100.000100.000

(Verdecchia et al. EJC 2001)(Verdecchia et al. EJC 2001)

Incidenza delle neoplasie Incidenza delle neoplasie ITALIA 2000 ITALIA 2000

proiezione per sesso ed età -proiezione per sesso ed età -

Incidenza neoplasie nell’anzianoIncidenza neoplasie nell’anzianoSedi più frequentiSedi più frequenti

Polmone

Prostata

Colon-retto

Vescica

Altri

Polmone

Mammella

Colon-retto

Utero

Altri

Uomini Donne

18,2

35,811,3

28,2

6,5

Età 65-74 aa

34,9

136,4

17,3

28,4

Fonte: NCI SEER Program e NPCRFonte: NCI SEER Program e NPCR

Incidenza neoplasie nell’anzianoIncidenza neoplasie nell’anzianoSedi più frequentiSedi più frequenti

Polmone

Prostata

Colon-retto

Vescica

Altri

Polmone

Mammella

Colon-retto

Utero

Altri

Età>75 aa

Uomini Donne

31,640

14,5

16,9

28,38,7

18,7

13,2

23,5

4,6

Fonte: NCI SEER Program e NPCRFonte: NCI SEER Program e NPCR

Average life expectancy 1580 - 2000

Max Plank Institute for Demography, Rostock, Germany, Annual Report 2001

1580-1810 ~ 7 yrs 36-43

1820-1870 ~ 11 yrs 43-54

1880-2000 ~ 30 yrs 54-84

Cancer risk increases with age

1,4

7,73

24,48

1,7

8,08

13,38

Male

Female

30

25

20

15

10

5

0 0–39 40–59 60–74

Age (years)

Cu

mu

lati

ve r

isk

in

Eu

rop

ean

Un

ion

(%

)

Ferlay J, et al. Eucan IARC CancerBase. Lyon:IARC Press; 1999. Updated September 29, 2000.

Cancer incidence and mortality + 65 vs - 65Cancer incidence and mortality + 65 vs - 65

Lyman G. Cancer Control. 1998;5:347-354.

30

20

10

0

–10

–20

–30

20

10

0

–10

–20

–30

Ch

ang

e (%

)

1950 1990 1950 1990Year Year

Ch

ang

e (%

)

Incidence Mortality

65

<65

<65

65

Cancer incidence and mortality are Cancer incidence and mortality are increased in the elderly (>65 years)increased in the elderly (>65 years)

Ferlay J, et al. Eucan IARC CancerBase. Lyon:IARC Press; 1999. Updated September 29, 2000.

Incidence Mortality

Ovarian Breast NHL Lung Colorectal Ovarian Breast NHL Lung Colorectal

Over 65

Under 65

NHL = non-Hodgkin’s lymphoma

Cas

es (

%)

0

20

40

60

80

100

Impact of Aging on Cancer

Comorbidity

Frailty

Anemia

Body&Metabolism Disfunctions

PolyPharmacy

0%

10%

20%

30%

40%

50%

60%

Per

cen

t

55-59 60-64 65-69 70-74 75-79 80-84 85+Age Group

Hypertension

Previous malignancy

Arthritis

High severity heart disease

Stroke/TIA

COPD

Diabetes

Heart disease, moderate

Comorbidity Prevalence in Cancer Patients by Age

Yancik R, Wesley M, Ries L, Havlik R, Edwards B, Yates, J, Effect of Age and Comorbidity in

Cancer Patients, JAMA, 2001, Vol 285, No.7, 885-892

Curve di sopravvivenza in relazione all’indice di comorbilità di Charlson

1 2 3 4 5 6 7 8 9 10

100 %

Anni di Follow-up

Score 0

Score 1

Score 2

Score 3

• Age > 85 years

• Dependence in one or more ADL

• Presence of three or more comorbidities

• Presence of one or more geriatric syndromes

Frialty: CriteriaFrialty: Criteria

Age (years)

Disabilityin ADL

Frailty

Aging, Fraility and Disability

Ref: Ferrucci L , unpublished 2000.

65

15% of the Elderly

Ph

ysic

al A

bili

ty o

r . .

.

100

Physiologic reserve - Hypothetical Trajectory to Illness, Functional Limitation & Disability

Younger age Older age

Ph

ysio

log

ic r

eser

ve

Time

hip fracture

pneumoniacongestiveheart failure

Functional limitation

Disability

Overlap of Frailty with chronic Overlap of Frailty with chronic diseases: a role for subclinical diseases: a role for subclinical

disease ?disease ?

Comorbidity

Frailty

Disability

Anemia: An Indipendent Risk Factor for Anemia: An Indipendent Risk Factor for DeathDeath

• Mortality risk is significantly increased in Mortality risk is significantly increased in individuals aged >70 years with anemiaindividuals aged >70 years with anemia11

• This increased risk is indipendent of This increased risk is indipendent of diseases at baseline, or functional diseases at baseline, or functional impairmentimpairment11

• Other data indicate that mortality is also Other data indicate that mortality is also increased in elderly individuals >65 increased in elderly individuals >65 yearsyears22

1. Izaks G, et al JAMA. 1999;281:1714 - 17172. Ania B, et al. J Am Geriatr Soc 1997;45:825-831

Marrow reserves

Cellularity

• 30% fat - young• 50% fat - normal

• 70% fat - elderly

Aging affects chemotherapy toxicity and effectiveness

• Pharmacokinetic changes that increase toxicity– decreased volume of distribution (Vd)– decreased glomerular filtration rate (GFR)– decreased hepatic metabolism

– decreased intestinal absorption

• Pharmacodynamic changes that limit effectiveness– increased expression of multidrug resistance (MDR) gene– decreased apoptosis– increased tumour anoxia– decreased cell proliferation

Balducci L, Carreca I, et al Oncologist. 2000;5:224-237.

test changeBody weight/fat + 35%

Plasmatic volume - 8%Albumine - 10%globulins - 10%

Total body water - 17%Extracellular fluids - 40%

Cardiac electric stym/velocity - 20%Cardiac capacity - 40%Ejection fraction - 35%

Vital capacity - 60%glomerular filtration - 50%

Renal/GI ematic circulation - 40%

Physiological Aging-related ChangesPhysiological Aging-related Changes(20 to 80 yrs)(20 to 80 yrs)

From Chung & Chang, J Surg Oncol, 2003

Survival of colorectal cancer elderly patients following surgical resection by serum IL-6 concentration

A NEGLECTED A NEGLECTED ISSUE: ISSUE: POLYPHARMACYPOLYPHARMACY

RISK OF DRUG INTERACTIONS INCREASES BY ABOUT 7-13%% PER DRUG USED, i.e. 100% risk at the 8th drug

Karas S Ann Emerg Med, 2001;10:627–30

Other Factors Influencing Other Factors Influencing Toxicities:Toxicities:

Polypharmacy:Polypharmacy:

o On average, adults over the age of 65 use 2-6 On average, adults over the age of 65 use 2-6 prescribed medications and 1-3 non-prescribed prescribed medications and 1-3 non-prescribed medicationsmedications

o Drugs used to treat other health problems may Drugs used to treat other health problems may interfere with chemotherapy regimensinterfere with chemotherapy regimens

BMJ, 2002, 324:1497BMJ, 2002, 324:1497

Fattori che contribuiscono alla polifarmaciaFattori che contribuiscono alla polifarmacia

Numero di patologie croniche Numero di patologie croniche

SessoSesso

Terapie prescritte da piu’ medici Terapie prescritte da piu’ medici ad es. specialisti. ad es. specialisti.

Automedicazione con farmaci Automedicazione con farmaci prescritti e OTC. prescritti e OTC.

Aumentata mobilita’ degli Aumentata mobilita’ degli anziani. anziani.

Messaggi pubblicitari diretti al Messaggi pubblicitari diretti al consumatore. consumatore.

Richieste da parte dei caregivers Richieste da parte dei caregivers o personale infermieristico. o personale infermieristico.

Prescrizioni telefoniche del Prescrizioni telefoniche del medico.medico.

I medici sono riluttanti a I medici sono riluttanti a sospendere terapie prescritte sospendere terapie prescritte da altri medici. da altri medici.

Raramente la terapia Raramente la terapia farmacologica e’ sottoposta a farmacologica e’ sottoposta a revisioni periodiche. revisioni periodiche.

"Start slow, Go slow" puo’ "Start slow, Go slow" puo’ portare a somministrazioni portare a somministrazioni sottodosate di farmaci con sottodosate di farmaci con insuccesso terapeutico.insuccesso terapeutico.

Comprehensive geriatric assessment reveals stages of aging

• Group 1Group 1– functionally independent, no serious comorbidity– standard cancer treatment

• Group 2Group 2– partially dependent, 2 comorbid conditions– modified cancer treatment

• Group 3Group 3– dependent,3 comorbid conditions, any geriatric

syndrome– palliative treatment

Balducci L, et al. Oncologist. 2000;5:224-237

Dependence

ADL IADLBathing

Dressing

Toileting

Transfer

Continence

Feeding

Using telephone

Shopping

Cooking

House keeping

Laundry

Trasportation

Medication

Handling finances

Comprehensive Geriatric Assessment (CGA)

Comorbidity(Charlson scale)

Cardiovascular diseases

Respiratory diseases

Hepatic impairment

Renal impairment

Other major organ failures

Hematological malignancies

Metastatic solid tumors

AIDS

Polipharmacy(causes)

Long-term medications

Unecessary prescriptions

Increased risk of interactions

Cognition(Mini Mental Status Examination)

Memory

Orientation

Comprehension

Logical thinking

Poor Nutrition(causes)

Anorexia/cachexia

Depression

Bad dentition

Cognitive impairment

Functional impairment

Lack of caregivers

Toxicity of chemotherapy

Geriatric Syndromes

Dementia

Delirium

Severe depression

Frequent falls

Spontaneous fractures

Balducci L, et al. Oncologist. 2000;5:224-237.

Assessment

Group 1

Life expectancy

>Cancer

Life-prolongingtreatment

Palliation

Group 2 Group 3

<Cancer

Treatmenttolerance

Yes No

AlphaMed Press 1083-7159.

Comprehensive Geriatric Assessment (CGA)

(frial elderly)

To TreatTo Treatoror

Not To TreatNot To Treat

ELDERLY ELDERLY PATIENTSPATIENTS

??

0102030405060708090

%

% tutti i paz. anziani con cancro % paz. anziani arruolati in RCT

Proporzione di pazienti anziani (>65 aa) arruolati in studi clinici controllati su terapie di diversi tipi di cancro, rispetto alla proporzione di anziani con la

stessa patologia nella popolazione generale(Hutchins LF, NEJM 1999)

EVIDENCE-BIASED MEDICINE

Elderly are almost systematically excluded from controlled studies.

Even if included, these studies show comparative efficacy of only some types of treatment, for an “average” randomized patient.

Sir John Grimley EvansUniversity of Oxford

Gambassi et al. RAYS 1999;24:26-31

The exclusion of older cancer patients from clinical trials

Gambassi et al. Giornale di Gerontologia 1999;47:51-5

Il grande vecchio è davvero un buco nero per la farmacologia clinica?

•Specifico su anziani (>75 aa) 3%

•Esclude anziani in maniera giustificabile 8%

•Esclude anziani in maniera non giustificabile 35%

•Non specifica i limiti di età 54%

Percentuale di articoli originali su studi clinici (tot. 1012) pubblicati su BMJ, Gut, Lancet, Thorax in 12

mesi riportanti dati ottenuti su pazienti anziani

Tra il 1966 ed il 1996 sono stati pubblicati solo 50 studi clinici specificamente disegnati per il paziente anziano, soprattutto nell’ipertensione (13), neuropsichiatria (11) e patologie cardiologiche (7)

UNDER-REPRESENTATION OF ELDERLY PTS WITH ADV. CRC IN CT TRIALS

58

60

62

64

66

68

70

72

74

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000

Me

dia

n a

ge

of C

RC

pa

tien

ts (

yea

rs)

Registry Clinical trials

Jennens RR et al., Intern Med J. 2006 Apr;36(4):216-20.

The median age of CRC pts enrolled in RCT remained constant (62.0 and 62.2 yrs), whilst the median age of the CRC population increased from 68.4 to 70.2 yrs

6.4 yrs 8.0 yrs

Undertreatment in elderly patients

• Aggressive lymphoma• older patients less likely to be treated for cure,

less likely to survive for 5 years

• Breast cancer– older women less likely to be invited into clinical trials

• Stage III colon cancer – older patients less likely to receive chemotherapy

• Lung cancer– older patients receive delay in diagnosis and less

aggressive treatmentChen C, et al. Leuk Lymphoma. 2000;38:327-334.

Kemeny M, et al. Proc Am Soc Clin Oncol. 2000; 19:602a, Abstract 237I.Mahoney T, et al. Arch Surg. 2000;135:182-185.

Peake M. Presentation at 96th International Conference of Am Thoracic Soc, Toronto, May 2000.

PFS/DFS by STUDY and AGE GROUP

CONCLUSION:FOLFOX4 maintains its efficacy and safety ratio in selected elderly pts with colorectal cancer. Its judicious use should be considered without regard to age, although scant data are available among pts older than 80 yrs.

CONCLUSION:FOLFOX4 maintains its efficacy and safety ratio in selected elderly pts with colorectal cancer. Its judicious use should be considered without regard to age, although scant data are available among pts older than 80 yrs.

<70 yrs >=70 yrs

(Goldberg R et al., JCO 2006; 2:4: 4085-91, modif.)

Incidenza di mucositeIncidenza di mucosite• CHEMIOTERAPIACHEMIOTERAPIA *(%)*(%)

– High-dose High-dose 75-10075-100

– Standard-dose Standard-dose 4040

• RADIOTERAPIARADIOTERAPIA 75-10075-100

• frequente nel corso di cure palliative frequente nel corso di cure palliative • comune in pazienti pediatrici e anzianicomune in pazienti pediatrici e anziani (incidenza 3-5 volte superiore che nell’adulto)(incidenza 3-5 volte superiore che nell’adulto)

Renal function

Cockcroft-Gault equation:

Kintzel and Dorr formula:

• Selezione del paziente mediante valutazioneSelezione del paziente mediante valutazione geriatrica completa.geriatrica completa.• Adattamento della dose iniziale ( funzionalità renaleAdattamento della dose iniziale ( funzionalità renale e cardiaca ).e cardiaca ).• Mantenimento dei livelli di Hb > 12g/dL con EpoMantenimento dei livelli di Hb > 12g/dL con Epo• Attuazione tempestiva di adeguata idratazione perAttuazione tempestiva di adeguata idratazione per controllare la mucosite.controllare la mucosite.• In età In età >> 65 anni uso profilattico dei CSF per tossicità 65 anni uso profilattico dei CSF per tossicità ematologica moderata-intensa.ematologica moderata-intensa.

In clinical practice…..In clinical practice…..

To TreatTo Treatoror

Not To TreatNot To Treat

ELDERLY ELDERLY PATIENTSPATIENTS

??

To TreatTo Treatoror

Not To TreatNot To TreatELDERLY ELDERLY PATIENTSPATIENTSYES,WE YES,WE

DO..DO..

… …Message to take home..Message to take home..

• Age is not a contraindication to full-dose Age is not a contraindication to full-dose therapytherapy

• Main limiting factors Main limiting factors – poor overall health and functionpoor overall health and function– presence of comorbiditiespresence of comorbidities

• Elderly are more susceptible to myelotoxicityElderly are more susceptible to myelotoxicity

• In elderly with good performance status,In elderly with good performance status,equal treatment yields equal benefitequal treatment yields equal benefit

• Prophylactic use of G-CSF helps maintainProphylactic use of G-CSF helps maintainchemotherapy dose intensitychemotherapy dose intensity