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					       Mediterranean School of Oncology
        Director :Prof.Stefano Iacobelli


  Impact of Patient Age on Treatment of CRC

Advanced Course: Highlights in the Management of CRC
                  Roma, 1-2 febbraio 2007
                    Domus Sessoriana

                       Prof.I.Carreca
              Chair of Medical Oncology,Chief
                University of Palermo-Italy
Elderly people………..?




   Young old: 65-74 years of age


  Older old: 75-84 years of age


 Oldest old: over 85 years of age
                       Incidenza delle neoplasie
                             ITALIA 2000
                               proiezione per sesso ed età -

              Frequenza per 100.000
      4000
                                                               25-29aa
      3500                                                     30-34aa
      3000                                                     35-39aa
                                                               40-44aa
      2500
                                                               45-49aa
      2000                                                     50-54aa
                                                               55-59aa
      1500
                                                               60-64aa
      1000                                                     65-69aa
       500                                                     70-74aa
                                                               75-79aa
          0                                                    80-84aa
                        Uomini                      Donne
(Verdecchia et al. EJC 2001)
     Incidenza neoplasie nell’anziano
            Sedi più frequenti

                  Età 65-74 aa


                  Polmone                            Polmone

          18,2    Prostata               17,3        Mammella
 28,2
                                34,9
                  Colon-retto                        Colon-retto
                                          28,4
6,5        35,8
   11,3           Vescica       6,4 13               Utero
                  Altri
                                                     Altri
 Uomini                            Donne


                                 Fonte: NCI SEER Program e NPCR
             Incidenza neoplasie nell’anziano
                        Sedi più frequenti


                             Età>75 aa

                     Polmone                               Polmone

             16,9    Prostata                 13,2         Mammella
31,6
                                       40
                     Colon-retto                    23,5   Colon-retto
              28,3
8,7                  Vescica                               Utero
      14,5                               4,6 18,7
                     Altri                                 Altri

       Uomini                               Donne


                                       Fonte: NCI SEER Program e NPCR
           Average life expectancy 1580 - 2000

                                                1880-2000
                                                 ~ 30 yrs
                                                  54-84




                                1820-1870
                                 ~ 11 yrs
                                  43-54


                                                       1580-1810
                                                        ~ 7 yrs
                                                         36-43




Max Plank Institute for Demography, Rostock, Germany, Annual Report 2001
                      Cancer risk increases with age

                     30         Male
                                Female                          24,48
European Union (%)



                     25
Cumulative risk in




                     20
                                                                        13,38
                     15

                     10                  7,73 8,08


                     5    1,4     1,7

                     0          0–39          40–59                       60–74
                                         Age (years)
                                            Ferlay J, et al. Eucan IARC CancerBase. Lyon:
                                           IARC Press; 1999. Updated September 29, 2000.
Cancer incidence and mortality + 65 vs - 65

                           Incidence                                       Mortality
              30                                          20
                                       65                                               65
              20                                          10
              10
 Change (%)




                                             Change (%)
                                       <65
                                                           0
               0                                                                          <65
                                                          –10
              –10

              –20                                         –20

              –30                                         –30
                    1950            1990                            1950               1990
                             Year                                           Year

                                                          Lyman G. Cancer Control. 1998;5:347-354.
             Cancer incidence and mortality are
             increased in the elderly (>65 years)
                                                                                         Over 65
                                                                                         Under 65
                              Incidence                                  Mortality

            100

             80
Cases (%)




             60

             40

             20

              0
                  Ovarian Breast   NHL   Lung Colorectal    Ovarian Breast   NHL   Lung Colorectal



                                                      Ferlay J, et al. Eucan IARC CancerBase. Lyon:
 NHL = non-Hodgkin’s lymphoma                       IARC Press; 1999. Updated September 29, 2000.
Impact of Aging
  on Cancer



                  Comorbidity
                  Frailty
                  Anemia
                  Body&Metabolism
                  Disfunctions
                  PolyPharmacy
Comorbidity Prevalence in Cancer Patients by Age
           60%



           50%                                                                        Hypertension

                                                                                       Heart disease,
                                                                                       moderate
           40%
                                                                                       High severity heart
                                                                                       disease
 Percent




           30%                                                                         Diabetes


                                                                                       Arthritis
           20%

                                                                                       Previous malignancy
           10%                                                                         Stroke/TIA

                                                                COPD
           0%
                 55-59    60-64      65-69     70-74   75-79        80-84     85+
                                             Age Group
                 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

100 %
                                              Score 0



                                              Score 1


                                              Score 2

                                              Score 3
                                                 Anni di
          1   2   3   4   5   6   7   8   9   10 Follow-up
Frialty: Criteria


              •   Age > 85 years
              •   Dependence in
                  one or more ADL
              •   Presence of three
                  or more
                  comorbidities
              •   Presence of one
                  or more geriatric
                  syndromes
                     Aging, Fraility and Disability

                                                         “ No
      Physical Ability or . . .
                                                             rm
                                                                     al ”
                                                                            Ag
                                                                              ing



                                               “A
                                                cc
                                                ele
                                                    ra
                                                       ted
                                                       ”A
                                  Frailty

                                                             gi
                                                                ng
                                  15% of the Elderly

                                  Disability
                                  in ADL


                                    65                                              100
                                                       Age (years)
Ref: Ferrucci L , unpublished 2000.
           Physiologic reserve - Hypothetical Trajectory
            to Illness, Functional Limitation & Disability

                                              hip fracture
Physiologic reserve




                                                          pneumonia
                                                                      congestive
                                                                      heart failure

                                                                               Functional

                                                                               limitation


                                                                               Disability




                      Younger age Older age
                              Time
     Overlap of Frailty with chronic
diseases: a role for subclinical disease ?



      Disability             Comorbidity




                   Frailty
Anemia: An Indipendent Risk Factor for Death



  • Mortality risk is significantly increased in
    individuals aged >70 years with anemia1
  • This increased risk is indipendent of
    diseases at baseline, or functional
    impairment1
  • Other data indicate that mortality is also
    increased in elderly individuals >65 years2
                     1.   Izaks G, et al JAMA. 1999;281:1714 - 1717
                     2.   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.
Physiological Aging-related Changes
           (20 to 80 yrs)
                           test    change
               Body 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%
 Survival of colorectal cancer elderly patients following
    surgical resection by serum IL-6 concentration




From Chung & Chang, J Surg Oncol, 2003
A NEGLECTED
ISSUE:
POLYPHARMACY




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
             Toxicities:
Polypharmacy:

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

o Drugs used to treat other health problems may
  interfere with chemotherapy regimens
BMJ, 2002, 324:1497
    Fattori che contribuiscono alla polifarmacia
 Numero di patologie croniche            Prescrizioni   telefoniche   del
                                           medico.
 Sesso
                                          I medici sono riluttanti a
                                           sospendere terapie prescritte da
 Terapie prescritte da         piu’       altri medici.
  medici ad es. specialisti.
                                          Raramente         la   terapia
 Automedicazione con farmaci              farmacologica e’ sottoposta a
  prescritti e OTC.                        revisioni periodiche.

                                          "Start slow, Go slow" puo’
 Aumentata       mobilita’    degli
                                           portare    a   somministrazioni
  anziani.                                 sottodosate di farmaci con
                                           insuccesso terapeutico.
 Messaggi pubblicitari diretti al
  consumatore.

 Richieste     da     parte   dei
  caregivers       o     personale
  infermieristico.
  Comprehensive geriatric assessment
       reveals stages of aging


• Group 1
  – functionally independent, no serious comorbidity
  – standard cancer treatment
• Group 2
  – partially dependent, 2 comorbid conditions
  – modified cancer treatment
• Group 3
  – dependent, 3 comorbid conditions, any geriatric
    syndrome
  – palliative treatment


                                 Balducci L, et al. Oncologist. 2000;5:224-237
      Comprehensive Geriatric Assessment (CGA)
Dependence                       Comorbidity                  Cognition
                                 (Charlson scale)             (Mini Mental Status Examination)
ADL          IADL
Bathing      Using telephone     Cardiovascular diseases      Memory
Dressing     Shopping            Respiratory diseases         Orientation
Toileting    Cooking             Hepatic impairment           Comprehension
Transfer     House keeping       Renal impairment             Logical thinking
Continence   Laundry             Other major organ failures
Feeding      Trasportation       Hematological malignancies
             Medication          Metastatic solid tumors
             Handling finances   AIDS

Geriatric Syndromes              Poor Nutrition               Polipharmacy
                                 (causes)                     (causes)
Dementia                         Anorexia/cachexia            Long-term medications
Delirium                         Depression                   Unecessary prescriptions
Severe depression                Bad dentition                Increased risk of interactions
Frequent falls                   Cognitive impairment
Spontaneous fractures            Functional impairment
                                 Lack of caregivers
                                 Toxicity of chemotherapy
    Comprehensive Geriatric Assessment (CGA)

                               Assessment



        Group 1                   Group 2                               Group 3
                                                                     (frial elderly)
                              Life expectancy

                   >Cancer                     <Cancer

                  Treatment
                  tolerance


Life-prolonging   Yes   No
                                                                Palliation
   treatment


                                    Balducci L, et al. Oncologist. 2000;5:224-237.
                                                                   AlphaMed Press 1083-7159.
 To Treat
     or
Not To Treat

 ELDERLY
 PATIENTS
     ?
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)
90
80
70
60
50
%




40
30
20
10
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                       a




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        % tutti i paz. anziani con cancro   % paz. anziani arruolati in RCT
 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 Evans
                                                    University of Oxford



Il grande vecchio è davvero un buco nero per la farmacologia clinica?
                                         Gambassi et al. Giornale di Gerontologia 1999;47:51-5


    The exclusion of older cancer patients from clinical trials
    Gambassi et al. RAYS 1999;24:26-31
Percentuale di articoli originali su studi clinici (tot.
1012) pubblicati su BMJ, Gut, Lancet, Thorax in 12
  mesi riportanti dati ottenuti su pazienti anziani


•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%



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
                                                       74



                                                       72



                                                       70
                  Median age of CRC patients (years)




                                                       68



                                                       66     6.4 yrs                                                                            8.0 yrs
                                                                                                             Registry   Clinical trials

                                                       64



                                                       62



                                                       60



                                                       58
                                                            1982   1984   1986   1988   1990   1992   1994    1996      1998              2000




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
Jennens RR et al., Intern Med J. 2006 Apr;36(4):216-20.
      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 treatment
                                              Chen 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
                                         <70 yrs                     >=70 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.

(Goldberg R et al., JCO 2006; 2:4: 4085-91, modif.)
      Incidenza di mucosite
• CHEMIOTERAPIA                                       *(%)
   – High-dose                         75-100

  – Standard-dose                      40

• RADIOTERAPIA
                                       75-100

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

Cockcroft-Gault equation:




Kintzel and Dorr formula:
            In clinical practice…..

• Selezione del paziente mediante valutazione
  geriatrica completa.
• Adattamento della dose iniziale ( funzionalità renale
  e cardiaca ).
• Mantenimento dei livelli di Hb > 12g/dL con Epo
• Attuazione tempestiva di adeguata idratazione per
  controllare la mucosite.
• In età > 65 anni uso profilattico dei CSF per tossicità
  ematologica moderata-intensa.
 To Treat
     or
Not To Treat

 ELDERLY
 PATIENTS
     ?
  To Treat
     or
Not To Treat
 ELDERLY
 PATIENTS
  YES,WE
    DO..
         …Message to take home..

• Age is not a contraindication to full-dose
  therapy
• Main limiting factors
  – poor overall health and function
  – presence of comorbidities

• Elderly are more susceptible to myelotoxicity
• In elderly with good performance status,
  equal treatment yields equal benefit
• Prophylactic use of G-CSF helps maintain
  chemotherapy dose intensity

				
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posted:6/25/2012
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