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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.

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Presentazione sul tema: "Mediterranean School of Oncology Director :Prof.Stefano Iacobelli Impact of Patient Age on Treatment of CRC Advanced Course: Highlights in the Management."— Transcript della presentazione:

1 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

2 Young old: years of age Older old: years of age Oldest old: over 85 years of age Elderly people………..?

3 Frequenza per (Verdecchia et al. EJC 2001) Incidenza delle neoplasie ITALIA 2000 proiezione per sesso ed età -

4 Incidenza neoplasie nellanziano Sedi più frequenti UominiDonne 18,2 35,8 11,3 28,2 6,5 Età aa 34,9 13 6,4 17,3 28,4 Fonte: NCI SEER Program e NPCR

5 Incidenza neoplasie nellanziano Sedi più frequenti Età>75 aa UominiDonne 31, ,5 16,9 28,3 8,7 18,7 13,2 23,5 4,6 Fonte: NCI SEER Program e NPCR

6 Average life expectancy Max Plank Institute for Demography, Rostock, Germany, Annual Report ~ 7 yrs ~ 11 yrs ~ 30 yrs 54-84

7 2003 Estimated US Cancer Cases* *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, Men 675,300 Women 658,800 32%Breast 12%Lung & bronchus 11%Colon & rectum 6%Uterine corpus 4%Ovary 4%Non-Hodgkin lymphoma 3%Melanoma of skin 3%Thyroid 2%Pancreas 2%Urinary bladder 20%All Other Sites Prostate33% Lung & bronchus14% Colon & rectum11% Urinary bladder6% Melanoma of skin4% Non-Hodgkin lymphoma4% Kidney3% Oral Cavity3% Leukemia3% Pancreas2% All Other Sites17%

8 2003 Estimated US Cancer Deaths* ONS=Other nervous system. *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, Men 285,900 Women 270,600 25%Lung & bronchus 15%Breast 11%Colon & rectum 6%Pancreas 5%Ovary 4%Non-Hodgkin lymphoma 4%Leukemia 3%Uterine corpus 2%Brain/ONS 2%Multiple myeloma 23%All other sites Lung & bronchus31% Prostate10% Colon & rectum10% Pancreas5% Non-Hodgkin4% lymphoma Leukemia4% Esophagus4% Liver/intrahepatic3% bile duct Urinary bladder3% Kidney3% All other sites22%

9 ISTAT Oct 24, 2006 Nel 2003 la speranza di vita alla nascita è pari a 77,2 anni per gli uomini e a 82,8 per le donne con uno scostamento marginale rispetto allanno prima (+0,1 per gli uni, -0,2 per le altre). Inoltre, stime su dati provvisori permettono di prevedere per gli anni 2004 e 2005, 77,7 e 77,8 anni per gli uomini, 83,7 e 84,3 anni per le donne.

10 Cancer risk increases with age –3940–5960–74 Age (years) Cumulative risk in European Union (%) Ferlay J, et al. Eucan IARC CancerBase. Lyon: IARC Press; Updated September 29, 2000.

11 Cancer incidence and mortality + 65 vs - 65 Lyman G. Cancer Control. 1998;5: –10 –20 – –10 –20 –30 Change (%) Year Change (%) IncidenceMortality 65 <65 65

12 Cancer incidence and mortality are increased in the elderly (>65 years) Ferlay J, et al. Eucan IARC CancerBase. Lyon: IARC Press; Updated September 29, IncidenceMortality Ovarian Breast NHLLung Colorectal Over 65 Under 65 NHL = non-Hodgkins lymphoma Cases (%)

13 Impact of Aging on Cancer Comorbidity Frailty Anemia Body&Metabolism Disfunctions PolyPharmacy

14 0% 10% 20% 30% 40% 50% 60% Percent 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,

15 Curve di sopravvivenza in relazione allindice di comorbilità di Charlson % Anni di Follow-up Score 0 Score 1 Score 2 Score 3

16 Age > 85 years Dependence in one or more ADL Presence of three or more comorbidities Presence of one or more geriatric syndromes Frialty: Criteria

17 Aging, Frailty and Disease Operational Definitions for Studies on Aging Slow, Harmonic Decline of Integrity and Function of Multiple Physiologic Subsystems Accelerated, Harmonic Decline of Integrity and Function of Multiple Physiologic Subsystems Rapid Declineof Integrity and Function of Selected Physiologic Subsystems Disability Threshold Aging Frailty Disease Time Disability Threshold

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19 Physiologic reserve - Hypothetical Trajectory to Illness, Functional Limitation & Disability Younger ageOlder age Physiologic reserve Time hip fracture pneumonia congestive heart failure Functional limitation Disability

20 Overlap of Frailty with chronic diseases: a role for subclinical disease ? Comorbidity Frailty Disability

21 Anemia: An Indipendent Risk Factor for Death Mortality risk is significantly increased in individuals aged >70 years with anemia 1 Mortality risk is significantly increased in individuals aged >70 years with anemia 1 This increased risk is indipendent of diseases at baseline, or functional impairment 1 This increased risk is indipendent of diseases at baseline, or functional impairment 1 Other data indicate that mortality is also increased in elderly individuals >65 years 2 Other data indicate that mortality is also increased in elderly individuals >65 years 2 1.Izaks G, et al JAMA. 1999;281: Ania B, et al. J Am Geriatr Soc 1997;45:

22 Marrow reserves Cellularity 30% fat - young 50% fat - normal 70% fat - elderly

23 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:

24 Drug distribution and absorption Marrow reserves

25 testchange 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% Physiological Aging-related Changes (20 to 80 yrs)

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30 From Chung & Chang, J Surg Oncol, 2003 Survival of colorectal cancer elderly patients following surgical resection by serum IL-6 concentration

31 A NEGLECTED ISSUE: POLYPHARMACY 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

32 Polifarmacia Limpiego di piu farmaci per pazienti con una o piu patologie. Limpiego di piu farmaci per pazienti con una o piu patologie. Somministrazione di piu farmaci spesso concomitante per il trattamento della stessa patologia. Somministrazione di piu farmaci spesso concomitante per il trattamento della stessa patologia. Utilizzazione di formulazioni farmaceutiche che comprendono piu principi attivi. Utilizzazione di formulazioni farmaceutiche che comprendono piu principi attivi. Limpiego di farmaci senza una apparente indicazione terapeutica. Limpiego di farmaci senza una apparente indicazione terapeutica. Trattamento degli effetti collaterali come una nuova patologia. Trattamento degli effetti collaterali come una nuova patologia.

33 Other Factors Influencing Toxicities: Polypharmacy: oOn average, adults over the age of 65 use 2-6 prescribed medications and 1-3 non-prescribed medications oDrugs used to treat other health problems may interfere with chemotherapy regimens

34 BMJ, 2002, 324:1497

35 Fattori che contribuiscono alla polifarmacia Numero di patologie croniche Numero di patologie croniche Sesso Sesso Terapie prescritte da piu medici ad es. specialisti. Terapie prescritte da piu medici ad es. specialisti. Automedicazione con farmaci prescritti e OTC. Automedicazione con farmaci prescritti e OTC. Aumentata mobilita degli anziani. Aumentata mobilita degli anziani. Messaggi pubblicitari diretti al consumatore. Messaggi pubblicitari diretti al consumatore. Richieste da parte dei caregivers o personale infermieristico. Richieste da parte dei caregivers o personale infermieristico. Prescrizioni telefoniche del medico. Prescrizioni telefoniche del medico. I medici sono riluttanti a sospendere terapie prescritte da altri medici. I medici sono riluttanti a sospendere terapie prescritte da altri medici. Raramente la terapia farmacologica e sottoposta a revisioni periodiche. Raramente la terapia farmacologica e sottoposta a revisioni periodiche. "Start slow, Go slow" puo portare a somministrazioni sottodosate di farmaci con insuccesso terapeutico. "Start slow, Go slow" puo portare a somministrazioni sottodosate di farmaci con insuccesso terapeutico.

36 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:

37 Dependence ADLIADL Bathing 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

38 Balducci L, et al. Oncologist. 2000;5: Assessment Group 1 Life expectancy >Cancer Life-prolonging treatment Palliation Group 2Group 3

39 To Treat or Not To Treat ELDERLY PATIENTS ?

40 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)

41 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 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?

42 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 nellipertensione (13), neuropsichiatria (11) e patologie cardiologiche (7)

43 UNDER-REPRESENTATION OF ELDERLY PTS WITH ADV. CRC IN CT TRIALS Jennens RR et al., Intern Med J Apr;36(4): 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

44 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: Kemeny M, et al. Proc Am Soc Clin Oncol. 2000; 19:602a, Abstract 237I. Mahoney T, et al. Arch Surg. 2000;135: Peake M. Presentation at 96th International Conference of Am Thoracic Soc, Toronto, May 2000.

45 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: , modif.)

46 Incidenza di mucosite CHEMIOTERAPIA *(%)CHEMIOTERAPIA *(%) –High-dose –Standard-dose 40 RADIOTERAPIA RADIOTERAPIA frequente nel corso di cure palliative frequente nel corso di cure palliative comune in pazienti pediatrici e anziani comune in pazienti pediatrici e anziani (incidenza 3-5 volte superiore che nelladulto) (incidenza 3-5 volte superiore che nelladulto)

47 Renal function Cockcroft-Gault equation: Kintzel and Dorr formula:

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

57 To Treat or Not To Treat ELDERLY PATIENTS ?

58 To Treat or Not To Treat ELDERLY PATIENTS YES,WE DO..

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60 …Message to take home.. …Message to take home.. Age is not a contraindication to full-dose therapy Age is not a contraindication to full-dose therapy Main limiting factors Main limiting factors –poor overall health and function –presence of comorbidities Elderly are more susceptible to myelotoxicity Elderly are more susceptible to myelotoxicity In elderly with good performance status, equal treatment yields equal benefit In elderly with good performance status, equal treatment yields equal benefit Prophylactic use of G-CSF helps maintain chemotherapy dose intensity Prophylactic use of G-CSF helps maintain chemotherapy dose intensity


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