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Treatment of Special Populations: Elderly and PS2 patients

Treatment of Special Populations: Elderly and PS2 patients Cattedra di Oncologia Medica e U.S. di OncoGeriatria, Policlinico Universitario di Palermo Dir. :Prof.I.Carreca onccar@unipa.it Highlights in the Management of NSCL Cancer Rome June,13-14 08 –MSO .

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Treatment of Special Populations: Elderly and PS2 patients

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  1. Treatment of Special Populations: Elderly and PS2 patients Cattedra di Oncologia Medica e U.S. di OncoGeriatria, Policlinico Universitario di Palermo Dir. :Prof.I.Carreca onccar@unipa.it Highlights in the Management of NSCL Cancer Rome June,13-14 08 –MSO Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone dell’Università degli Studi di Palermo

  2. Elderly people………..Problem Entity? Young old: 65-74 years of age Older old: 75-84 years of age Oldest old: over 85 years of age

  3. Frequenza per 100.000 Incidenza delle neoplasie ITALIA 2006 proiezione per sesso ed età (Verdecchia et al. EJC 2006)

  4. 50 - 69 vs 70 - 84Lung Cancer:Incidence&Mortalityt (1/100.000 ) Prof. I. Carreca – Università degli Studi di Palermo Source: Micheli A,et al. Current cancer profiles of the Italian Regions. Tumori 93(4), 2007

  5. Q. ConcurrentCauses Smoke Alcohol Low mobility

  6. Industrial Pollution Incidence of Most Cancers 1930 1950 1970 1990 Year

  7. Avoid Carcinogens at Work Some Carcinogens in the Workplace

  8. Troubles In Treating ELDERLY PATIENTS

  9. Impact of Aging on Cancer Comorbidity Anemia Body&Metabolism Disfunctions PolyPharmacy Frailty Therapy

  10. 60% Hypertension 50% Heart disease, moderate 40% High severity heart disease Percent Diabetes 30% Arthritis 20% Previous malignancy Stroke/TIA 10% COPD 0% 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age Group 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

  11. COMORBIDITY INDEX AND SCORE OF CHARLSON & al CONDITION ASSIGNED WEIGHT • liver disease mild 1 • diabetes 1 • hemiplegia 2 • renal disease moderate or severe 2 • diabetes with end organ damage 2 • any malignancy 2 • leukemia 2 • malignant lymphoma 2 • liver disease. moderate or severe 3 • metastatic solid malignancy 6 • AIDS 6

  12. COMORBIDITY INDEX AND SCORE OF CHARLSON & al...(continued) CONDITION ASSIGNED WEIGHT • myocardial infarction1 • congestive heart failure 1 • peripheral vascular disease 1 • cerebrovascular disease 1 • dementia 1 • chronic pulmonary disease 1 • connective tissue disease 1 • ulcer disease 1

  13. 100 % 1 2 3 4 5 6 7 8 9 10 Charlons’index related OS Score 0 Score 1 Score 2 Score 3 Years Follow-up

  14. Incidence of Anemia in Cancer Patients Anemia Grade 1 or 2 Anemia Grade 3 or 4 50 43.9 45 41.1 40.0 39.5 39.5 40 37.5 35 30 25.9 25 Patients (%)‏ 20 16.3 14.1 14.0 15 12.4 8.4 10 8.3 4.9 5 0 Lung Cancer Metastatic Advanced Lymphomas Advanced Advanced Head Total Colorectal and Neck Breast Cancer Ovarian Cancer Cancer Cancer Groopman JE, Itri LM. J Natl Cancer Inst. 1999;91:1616–1634.

  15. Marrow reserves • Cellularity • 30% fat - young • 50% fat - normal • 70% fat - elderly

  16. 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.

  17. 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% Physiological Aging-related Changes(20 to 80 yrs)‏

  18. Lung Cancer in Elderly(types frequence) • 171,600 new cases reported; 158,900 deaths anticipated. • > 80% will be Non-small Cell types • >70% have Stage III/IV disease at diagnosis Cancer Statistics 1999, CA 49:8-31, 1999.

  19. Troubles in treatment • Early micrometastasis • Inherited and acquired resistance to radiation and chemotherapy • Late diagnosis • Co-morbidity

  20. Intestinal absorption in elderly ↓ gastric pH ↓ digestive enzymes ↓ gastric emptying ↓ splanchnic blood flow impaired mucosa

  21. Creatinine Clearance and Aging Hosoya T, et al Intern Med. 1995; 34(6): 520-7.

  22. Renal Excretion • Drugs completely excreted through the kidneys: • Methotrexate (*use with extreme care) • Carboplatin • Drugs partially excreted through the kidneys: • Epipodophyllotoxins • Fludarabine • Capecitabine • Pemetrexed • Drugs producing active or toxic metabolites excreted through the kidneys: • Cytarabine (high doses)

  23. Hepatic Metabolism and Age: P450 • Liver flow reduced • Liver size decreases • Age related changes in P450 microsomal systems • Polypharmacy* • P450 inhibitors: grapefruit juice • P450 inducers: phenobarbital CYP3A *Ref: David Flockhart, MD, http://medicine.iupui.edu/flockhart/

  24. Chemotherapy P450 Metabolism

  25. Comprehensive Geriatric Assessment (CGA)

  26. 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, ³3 comorbid conditions, any geriatric syndrome • palliative treatment Balducci L, et al. Oncologist. 2000;5:224-237 L. Balducci & W. B. Ershler Nature Reviews Cancer 5, 655-662

  27. Caravaggio St Jerome (1605-06)Oil on canvas, 118 x 81 cmMonastery, Montserrat Frailty Criteria Age > 85 years Dependence in one or more ADL Presence of three or more comorbidities Presence of one or more geriatric syndromes

  28. Management of elderly cancer patients Assessment Group 1 Group 2 Group 3 Life expectancy >Cancer <Cancer Treatmenttolerance Life-prolongingtreatment Palliation Yes No Balducci L, et al. Oncologist. 2000;5:224-237.  AlphaMed Press 1083-7159.

  29. IS THERE OPTIMAL TXFOR THE ELDERLY WITH ADVANCED NSCLC?

  30. Should Older Patients Receive Combination Chemotherapy For Advanced Stage Non-Small Cell Lung Cancer (NSCLC)? An Analysis of Southwest Oncology Trials 9509 and 9308Karen Kelly, Sheryl Giarritta, Stephen Hayes, Wallace Akerley, Paul Hesketh, Antoinette Wozniak, Kathy Albain, John Crowley, David R. Gandara

  31. OBJECTIVES To determine the effect of age > 70 on survival, toxicity, and drug delivery in patients with a good performance status (PS) 0 - 1 receiving combination chemotherapy for advanced stage NSCLC.

  32. METHODS SWOG 9509 Paclitaxel + Carboplatin versus Vinorelbine + Cisplatin SWOG 9308 Vinorelbine + Cisplatin versus Cisplatin A retrospective analysis was conducted on two recent SWOG trials in advanced NSCLC:

  33. METHODS 1. The analysis identified two age groups: patients < 70 years of age and patients > 70 years of age. 2. The cohorts were compared for: a) baseline characteristics b) efficacy of treatment c) toxicity d) drug delivery

  34. Toxicity * p-value for all grades of toxicities

  35. CONCLUSIONS 1. Relatively few older patients (19%) entered these cooperative group trials. 2. There was a trend toward shorter survival in older patients (p=.06). 3. Grade 3-5 toxicities occurred more frequently in older patients (p=.06).

  36. CONCLUSIONS 4. Fewer patients of any age were able to complete VC compared to PCb. 5. A significantly larger number of older patients discontinued VC due to toxicity as compared to PCb. 6. Trials should be specifically designed for this population.

  37. TAX326: Study Design Docetaxel 75 mg/m2 IV + Cisplatin 75 mg/m2 IV q 3 wk RANDOMIZE • : Stratification by • Stage (IIIB or IV) • Geographic region Docetaxel 75 mg/m2 IV + Carboplatin AUC 6 IV q 3 wk Vinorelbine 25 mg/m2 IV 1, 8, 15, 22 + Cisplatin 100 mg/m2 IV d 1 q 4 wk Premed: Dexamethasone 8 mg PO bid  6 doses (first dose 12 hours prior to Docetaxel infusion) for the Docetaxel groups. Fossella FV. Eur J Cancer 2001;37(suppl 6):S154.

  38. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Docetaxel Cisplatin Vinorelbin Cisplatin P = 0.044(adjusted log-rank) Cumulative Probability 0 3 6 9 12 15 18 21 24 27 30 33 Survival Time (Mos.) TAX326 SURVIVAL All patients D+CIS VS. V+CIS: Non-inferiority vs improved survival

  39. FUTURE PLANS SWOG 0027 A phase II trial of vinorelbine followed by docetaxel in advanced NSCLC patients with a PS of 2 or Age > 70 years old Vinorelbine 25 mg/m2, d 1 & 8 every 3 weeks x 3 Docetaxel 35 mg/m2 weekly 3/4 weeks x 3

  40. NON-PLATINUM TXIN ELDERLY WITH NSCLC

  41. Randomized Trials in Elderly NSCLC Trial Group Comment V vs BSC ELVIS Completed GV vs V SICOG Completed G vs V vs GV ITA-MILES Completed

  42. Navelbine in the Elderly: Summary • E.L.V.I.S.: first Phase III trial demonstrating a survival advantage for single-agent chemotherapy vs BSC • Navelbine is generally well tolerated in the elderly patient • Age does not appear to change or increase toxicity • Greater sensitivity of some older individuals cannot be ruled out

  43. Gemcitabine Plus Vinorelbine vs Vinorelbine Alone in Patients with NSCLC: SICOG Study • Patients with Stage IIIB/IV NSCLC • Age  70 years at diagnosis • Randomized to: • Vinorelbine 30 mg/m2 d1, 8 q 3 weeks vs. • Vinorelbine 30 mg/m2 d 1, 8 • Gemcitabine 1250 mg/m2 d 1, d 8 administered q 3 weeks

  44. Chemotherapy in Elderly Patients with Advanced NSCLC Author Regimen N Response MS (mo) 1 YR 6.5 Gridelli* Vinorelbine 78 20% 32%* BSC 76 --- 14% 4.9 7 Frasci‡ Gemcitabine + Vinorelbine 76 22% 30%* Vinorelbine 76 15% 13% 4.5 *Gridelli, J Natl Cancer Inst 1999; 85:365-376. ‡Frasci et al, Proc ASCO 2001, 19:A1895 *p<0.05

  45. The MILES Phase III Trial: Gemcitabine + Vinorelbine vs Vinorelbine and vs Gemcitabine in Elderly Advanced NSCLC Patients RANDOMI ZE Vinorelbine 30 mg/m2 d1,8 Q 3 weeks NSCLC 70+ years old Chemotherapy naïve Stage IIIB (N3 or pleural effusion) or IV PS 0-2 Gemcitabine 1200 mg/m2 d1,8 Q 3 weeks Gemcitabine 1000 mg/m2 d1,8 Vinorelbine 25 mg/m2 d1,8 Q 3 weeks Gridellii et al.ASCO 2001 Abstract 1230

  46. MILES Trial - Conclusions • Polychemotherapy with gemcitabine + vinorelbine does not improve outcomes compared to single-agent vinorelbine or gemcitabine • Single-agent chemotherapy should remain a standard for advanced NSCLC elderly patients • Baseline QoL predictive of outcome, though no difference observed in Qol or IADL between each arm ASCO 2001 Abstract 1230 ORAL PRESENTATION

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