Special Populations Clinical Trials and Elderly Cancer Patients

Special Populations: Clinical Trials and Elderly Cancer Patients Stuart M. Lichtman, MD, FACP Associate Attending Memorial Sloan-Kettering Cancer Center Cancer Leading Cause of Death-Jan 05 Age Specific Cancer Incidence Rates Cancer Mortality and Mortality Rates Incidence of 10 Major Cancers in Patients Over 65 years (’73-’95) 80 70 60 50 40 30 20 10 0 y ar ov st ea a br om ph ng lu h ac m sto r de ad s bl a re nc pa n lo co te ta os pr ct re ly m um Modified from Yancik and Ries, Hematology Oncology Clin NA 2000 14:17 percent % % US Population 65 and older Percent 20 20 15 10 9.5 12 12.6 13.1 5 0 1965 1985 1990 2005 2025 Life Expectancy: Woman Life Expectancy (years) Age 65 70 75 80 85 Healthy 20.0 15.8 12.1 8.8 6.1 Average 18.5 14.8 11.5 8.4 5.9 Sick 9.7 8.6 7.3 5.9 4.5 Life Expectancy: Woman Life Expectancy (years) Age 65 70 Healthy 20.0 15.8 Average 18.5 14.8 Sick 9.7 8.6 75 80 85 12.1 8.8 6.1 11.5 8.4 5.9 7.3 5.9 4.5 Life Expectancy: Woman Life Expectancy (years) Age 65 70 Healthy 20.0 15.8 Average 18.5 14.8 Sick 9.7 8.6 75 80 85 12.1 8.8 6.1 11.5 8.4 5.9 7.3 5.9 4.5 The facts… • 60% of cancer is in people greater than 65 years of age • 70% of cancer mortality is in people greater than 65 years of age Therefore… • • • • • More older patients Living longer Living healthier More indications for anticancer therapy Many more patients in need of getting more therapy Geriatric Oncology • How is cancer treatment studied? – Primarily middle aged patients; minimal inclusion of older patients – Minimal comorbidity; patients with other medical problems excluded – Caucasian – Cancer center based; little community involvement Newsday, March 2 2004 One Person Household 75 or older Newsday, March 2 2004 More 213,000 than One person 75 or older 253,000 While they’re living longer and leading more robust lives, their increasing numbers will put added pressure on limited government resources. Newsday, April 19, 2004 How is cancer treatment studied? – Primarily middle aged patients; minimal inclusion of older patients – Minimal comorbidity; patients with other medical problems excluded – Caucasian – Cancer center based Elderly and Registration Trials Talarico, L. et al. J Clin Oncol; 22:4626-4631 2004 Fig 1. Proportion of elderly patients enrolled onto registration trials compared with the proportion of elderly patients in the US cancer population Elderly and Registration Trials Talarico, L. et al. J Clin Oncol; 22:4626-4631 2004 Fig 2. Proportion of elderly patients (> 65 years) enrolled onto registration trials compared with the proportion of elderly patients in the US cancer population C rci n o e oc p i oc y c fa rAyO i ga C h n llo t ©t i m ny S i e l o g NCI Sponsored Trials by Age J Clin Oncol 20:2109-2117, 2002 NCI Sponsored Trials Essentially no data for patients 80+ J Clin Oncol 20:2109-2117, 2002 Topics • Pharmacology • Design Issues • Clinical Trials Reporting Pharmacology • • • • Absorption Distribution Metabolism Excretion Absorption • Factors that may affect absorption – Controllable • Concomitant medication, ie. H2 blockers, antacids • Compliance – Not Controllable • Reduced gastric secretion, gastric emptying, gastrointestinal motility • Diminished splanchnic blood flow • Decreased absorption surface Distribution • Changes in body composition – fat content doubles – decreased intracellular water – albumin concentrations reduced (etopside, taxanes are highly protein bound) – anemia • Increase in volume of distribution • Lower peak concentration and prolonged terminal t½ 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/ Medications Median number per patient (range) # interacting with P450 6 (0-17) 2 (0-8) Potential for drug interactions, toxicity, ADR Extermann, et al. ASCO 2003 Metabolism and P450 • Drug interactions extremely important issue in elderly – Increases risk of hospitalization and dependency • Emphasizes the importance of minimizing concomitant medications • ?Role of different isoenzymes: genetic influences • ?Role of nonP450 medications Chemotherapy P450 Metabolism Agent Cyclophosphamide Docetaxel Doxorubicin Etoposide(+2E1) Mitoxantrone Paclitaxel (+2C8) Vinblastine Vincristine x x x x x x x (x) 1A2 2C9 2C19 x 2B6 x 2D6 3A4 x x Excretion • Decline in glomerular filtration rate (GFR) is one of the most predictable changes associated with aging • Additional effect of comorbid conditions on renal function Renal Excretion • Drugs completely excreted through the kidneys: – Methotrexate – Carboplatin • Drugs partially excreted through the kidneys: – Epipodophyllotoxins – Fludarabine – Capecitabine – Pemetrexed • Drugs producing active or toxic metabolites excreted through the kidneys: – Cytarabine (high doses) Sample CrCl Calculations Cockcroft-Gault: Female Age 70 70 70 70 80 80 80 Wt (kg) 70 70 70 50 70 70 50 Serum Cr 1.0 1.5 2.0 2.0 1.0 2.0 2.0 CrCl (cc/min) 58 39 29 21 50 25 18 Sample CrCl Calculations Using Cockcroft-Gault:Female Age 70 70 70 70 80 80 80 Wt (kg) 70 70 70 50 70 70 50 Serum Cr 1.0 1.5 2.0 2.0 1.0 2.0 2.0 CrCl (cc/min) 58 39 29 21 50 25 18 CrCl: Which formula? • • • • Cockcroft-Gault Jelliffe Levey: MDRD or aMDRD Wright • Clinical Consequences – May alter clinical trial eligibility or exclude patient from standard therapy – Misperception of drug safety, I.e. cisplatin Pharmacology • Pharmacokinetics – Little evidence of PK changes based on age alone – Changes (variability) are result of: • Comorbidity – Endorgan dysfunction – Physical factors: fat, anemia, albumin, etc. • Polypharmacy • Gender, ethnicity, genotype Influence of pharmacokinetics Shah, Br J Clin Pharmacol 2004 Pharmacodynamic • Heterogeneity of Effect – Tremendous variability in toxicity – Increased susceptibility • • • • Myelosuppression Mucositis Cardiac toxicity Nervous system toxicity Design Issues Design Issues • • • • Patient Selection Endpoints Dose Limiting Toxicity Toxicity Evaluation Patient Selection • Which older patient? • Comorbidity – Endorgan dysfunction: renal, hepatic – Cardiac disease – Neuropathy – Prior malignancy, i.e. prior chemotherapy, radiotherapy Which Older Patient?: Stages of Aging Primary/Healthy •No activity limitations •Reduced functional reserve Intermediate/ Vulnerable Secondary or frailty Near Death •Functional reserve critically reduced •Functional limitations •Some recovery possible •No recovery of functional reserve •Severe limitations •No functional reserve Hamerman D: Toward an understanding of frailty. Ann Intern Med 130:945-50, 1999 Patient Selection: Stages of Aging Primary/Healthy •No activity limitations •Reduced functional reserve Intermediate/ Vulnerable Secondary or frailty Near Death •Functional reserve critically reduced •Functional limitations •Some recovery possible •No recovery of functional reserve •Severe limitations •No functional reserve Hamerman D: Toward an understanding of frailty. Ann Intern Med 130:945-50, 1999 Comorbidity and Function • Comorbidity evaluation – Prevalent in elderly – Can predict survival – Various scales: Charlson, Cumulative Illness Rating Scale-Geriatric (CIRS-G) • Function – – – – – Can predict survival ADL, IADL Physical function: gait speed, get-up-and-go, etc. Dependency Should we or can we evaluate the frail patient? Design Issues: Endpoints • Survival – Is the patient going to die of or with cancer? • Response – Overall response – Freedom from progression – Time without symptoms • Functional and clinical benefit, quality of life Design Issues: DLT • Hematologic – Modulated by growth factors • Nonhematologic – Predominating – Are our toxicity scales adequate for older patients? • Function Non-hematologic Toxicity Evaluation-CTC v2 Toxicity Evaluation: Functional Toxicity Evaluation-Frail Proposed Toxicity Assessment • Peripheral sensory neuropathy – Oxaliplatin, vinca alkaloids, paclitaxel • Sequelae of neuropathy in older patients – Falls, social isolation (not driving), chronic impairment • Incorporate other measures – Hand grip – Get up and go; gait speed Functional Assessment as Endpoint • Alterations in: – ADL – IADL – Geriatric syndromes • Falls, delirium, incontinence, nutrition • Maintain independence/avoid further dependence Comprehensive Geriatric Assessment Is Highly Sensitive to Common Problems in Elderly • Findings among 200 patients age 70: – dependent in ADL 18% – dependent in IADL 72% – serious comorbidity 36% on Charlson scale 94% on CIRS-G scale – memory disorder 22% – poor nutrition 19% – polypharmacy 41% • Conclusion: CGA indicated in all patients age 70 Balducci L, et al. Oncologist. 2000;5:224–237. Comprehensive Geriatric Assessment Is Highly Sensitive to Common Problems in Elderly • Which assessment should be done and included? • CGA • Limited • Validating limited assessment • Hurria, et al. Cancer 2005 • CALGB and MSKCC Design Issues • Polypharmacy – Beer’s list (Fick, et al. 2003) • Minimize ADR • Modulate effects of drug interactions • Sampling – Limited sampling strategies • Minimize visits • Increase compliance Progressively Increasing Inclusion Criteria (PIIC) protocol design: Extermann • Rationale – Older patients are underrepresented in cancer trials. – The selected healthy patients that are enrolled appear in most cases to do roughly as well as younger patients with their treatment. – Category of vulnerable elderly patients, but an evidence-based definition is still lacking in oncology. Progressively Increasing Inclusion Criteria (PIIC) protocol design: Extermann • Rationale (cont) – Studies focused on patients in poor condition (typically ECOG PS 2), accrue poorly, probably due to the low prevalence of such patients in the population seen in centers and reluctance to enter – Geriatric instruments such as IADL, GDS, comorbidity, etc… appear to add prognostic information to ECOG PS, but cut-offs for chemotherapy modifications have not yet been determined. Progressively Increasing Inclusion Criteria (PIIC) protocol design: Extermann • Objective – Provide a study design that would allow establishing clinical cut offs for treatment modifications and response categories. • Eligibility – – – – Age 70 and above Stage IV NSCLC No previous chemotherapy for metastatic disease Cohort I: ECOG PS 0-1, independent in IADL (2829), Charlson <2 – Cohort II: ECOG PS 0-1, IADL 21-27 (mild dependence) or Charlson 2 – Cohort III: IADL <21, Charlson > 2, or ECOG PS 2 Publications in Geriatric Oncology Report of Clinical Trials • Journals – Journal of Clinical Oncology – Journal of the National Cancer Institute – Cancer • Criteria – January 2005-December 2006 – Prospective clinical trials – At least 50 patients Data • Papers reviewed: – 258 JCO, 58 Cancer, and 17 JNCI • The median number of patients enrolled per trial into these studies is – 212 (JCO), 77.5 (Cancer), and 954 (JNCI). • Mean age: 59.4 years (range 16 to 93 years). Data JCO Stratified by Age Cancer JNCI 7 (41%) 54 (20.9%) 17 (29.3%) Age in Analysis 75 (29%) 14 (24%) 6 (35.3%) 6 (35.3%) Age in 40 (15.5%) 8 (13.8%) Discussion Barriers to Participation • Fewer trials available – Focus on aggressive therapy – Trial eligibility limits participation, ie. comorbidity, previous malignancy • Limited expectation of benefit • Physician reluctance to recruit older patients and recommend protocols • Complicate trials requiring large expenditure of time for patients and caregivers Conclusions • 1)Drugs, which will be primarily used by older patients, should be studied in older patients. These studies should involve pharmacokinetic analysis and oral medication should include measurements of compliance; • 2) randomized phase II trials of new agents in groups of patients divided by age. These studies should involve pharmacokinetic analysis; • 3)dose modify in a phase I fashion using progressive degrees of functional impairment and increasing comorbidity; • 4)include functional independence as a clinical benefit of cancer treatment in older individuals; Conclusions • 5)consider studying long term functional and medical consequences of cancer treatment in long term older cancer survivors. • 6)Journal editors should encourage the inclusion of age related analyses in the reporting of clinical trials to provide meaningful information for clinicians caring for older patients. • 7)Clinical trial design of adult cancer patients should prospectively incorporate age analysis to maximize data generated Thank You Supplemental Slides Comorbidity is Key Factor Aec mr i i g - o obdty S oe cr 01 2 3 4 5 n 39 6 16 3 19 0 4 2 2 9 n cu l 1 y a At a 0 e r Sr i a ( ) uvv l % 9- 9 79 8 7 7 9 4 7 3 4 from Charlson et al, J Chron Dis 40:373, 1987 Burden of Comorbidity Yancik •Variety of comorbidities – – – – hypertension heart disease arthritis gastrointestinal problems – anemia – eye problems – – – – – – urinary tract problems previous cancers gall bladder problems COPD diabetes thyroid/glandular Burden of Comorbidity Yancik • Patients with >5 comorbid conditions – 55-65 years – 66-74 years – 75+ years 13% 24% 39% Burden of Comorbidity Yancik • Predictors of early mortality (24 months) with colon cancer Disorder heart disease COPD renal failure liver disease RR 1.31 1.51 1.73 2.54 Effect of Comorbidity of 3 Year Survival with Breast Cancer Mortality v. Comorbidity All Causes Breast Cancer Other Causes Ratio of Breast Cancer/ Other 0 1 2 3+ *p<.001 47.7 68.6 *108.3 *188.4 34.0 41.0 47.4 40.3 8.3 24.3 *56.2 *162.6 4.1 1.7 0.8 0.3 Satariano, & Ragland, Ann Intern Med, 1994. Geriatric Syndromes          Delirium Dementia Incontinence Falls Pressure ulcers Malnutrition Osteoporosis Language Hearing and vision  Sleep Activities of Daily Living (ADL)       Toilet Feeding Dressing Grooming Ambulation Bathing Instrumental ADL (IADL)        Telephone Shopping Food preparation Housekeeping Laundry Transportation Medication 2-year mortality rate for persons aged 70 years and older  8% if fully independent,  14% if dependent in IADL,  27% if dependent in ADL,   40% if institutionalized. • Reuben Am J Med 1992;93:663 Frailty • Age ≥85 • 3+ comorbidity • 1+ geriatric syndrome(s) • 1+ ADL • Biologic markers: ddimer, IL-6 Survival by Functioning 120 100 70 + independent Stage II % of patients 80 Frail 60 40 20 0 0 3 6 9 12 18 24 Months Rockwood et al. Lancet, 1998. Guidelines for Management of the Older Cancer Patient: The Assessment • • • • • • • Function Comorbidity Cognition Nutrition Pharmacy Socioeconomic status Geriatric syndromes Aging Physiology and Cancer Ai g hs l g g Pyi oy n o C crReac a e e vne n l  Srey u r g  a C,m V2 M O a O  x x x t a  ad pl oayuci n T i iyo er adug  r i u nr f n o o c t h t n l ns C o m t Srey u r g  on h ln  ud e i g W a R ad g xrto e l r ecei n n u F  R G tt a r  at ,s e ,s lvr fo N r i nrd to t eay  se m a ayl w u i o, ai i nh p T l l i r dr tn u s bi  en u l ms oy D g i t i uo  a mc a , bd L se s ft a Metabolism and P450 • Drug interactions extremely important issue in elderly – Increases risk of hospitalization and dependency • Emphasizes the importance of minimizing concomitant medications • ?Role of different isoenzymes: genetic influences • ?Role of nonP450 medications • ?Any toxicity specificity April 20, 2006 Paclitaxel Clearance by Age 30 Paclitaxel Clearance 20 10 0 50 55 60 65 70 Age 75 80 85 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) Creatinine Clearance and Aging Cockcroft-Gault formula Creatinine clearance (cc/min) = (140-age) x body weight (kg) 72 x serum creatinine (mg/dl) x 0.85 (women) Sample CrCl Calculations Cockcroft-Gault: Female Age 70 70 70 70 80 80 80 Wt (kg) 70 70 70 50 70 70 50 Serum Cr CrCl (cc/min) 1.0 58 1.5 39 2.0 29 2.0 21 1.0 50 2.0 25 2.0 18 Sample CrCl Calculations Using Cockcroft-Gault:Female Age 70 70 70 70 80 80 80 Wt (kg) 70 70 70 50 70 70 50 Serum Cr CrCl (cc/min) 1.0 58 1.5 39 2.0 29 2.0 21 1.0 50 2.0 25 2.0 18 Renal Dysfunction National Kidney Foundation Stage 1 2 3 4 5 Description Kidney damage with normal or increased GFR Mild decrease in GFR Moderate decrease in GFR Severe decrease in GFR Kidney failure GFR (mL/min 1.73 m2)  90 60–89 30–59 15–29 <15 or dialysis per Levey, et al. 2005 International Society of Geriatric Oncology Renal Taskforce (prelim) • Prior to drug therapy optimisation of hydration status and evaluation of renal function to establish any need for dose adjustment is required. • Serum creatinine alone is insufficient as a means of evaluating renal function. • More accurate tools, including creatinine clearance methods such as C-G are available and are generally good indices of renal function status of the patient. International Society of Geriatric Oncology Renal Taskforce (prelim) • In extremes of obesity and cachexia and at very high and low creatinine values, no single tool is really accurate. • Within each drug class, preference may be given to agents less likely to be toxic to the kidneys or for which appropriate methods of prevention for renal toxicity exist. • Co-administration of known nephrotoxic drugs such as bisphosphonates, NSAIDS or Cox-2 inhibitors should be avoided or minimised. Are elderly cancer patients under treated? Stuart M. Lichtman, MD Memorial Sloan-Kettering Cancer Center GOG July 2006 What is under treatment? • Poor evaluation? • Poor treatment? – Surgery – Radiation – Chemotherapy Under treatment • Question needs to be answered in terms of: – Goal of therapy – Potential benefit of therapy-what is the best possible outcome? Goal • Palliative – No potential for cure • Curative therapy exists – Patient cannot tolerate potentially curable therapy • Who decides • How is this decided • “self fulfilling prophesy” Curative therapy • • • • Adjuvant breast Adjuvant colon Advanced ovarian cancer Large cell lymphoma Adjuvant Treatment of Colon Cancer SEER Database • From 1998-2002, the median age at diagnosis for cancer of the colon and rectum was 72 years of age. • Approximately 29.2% between 75 and 84; and 12.6% 85+ years of age. Age-Specific SEER Incidence Rates by Sex for Colon and Rectum Cancer, 1998-2002 Questions being asked • Do older patients receive adjuvant chemotherapy? • Do older patients benefit from adjuvant therapy? Age and Adjuvant Chemotherapy Use After Surgery for Stage III Colon Cancer Schrag, et al. JNCI 2001 Questions being asked • Do older patients receive adjuvant chemotherapy? • Do older patients benefit from adjuvant therapy? N Engl J Med, 2001 Colon Cancer-Adjuvant Age NOT A Factor Survival Sargent, et al. NEJM 2001 Recurrence Phase III MOSAIC Trial: Adjuvant Oxaliplatin FOLFOX4 6 months (12 cycles) R LV/5-FU2 (de Gramont) Aim: 25% decrease in recurrent risk at 3 years (Expect 3-year DFS: 79% vs 73%) 148 Centers 20 Countries Median age: 60-61 Andre, 2004 Sargent, et al. 2006 FOLFOX in > 70 Year Olds • • • • • 3700 patients in 4 trials 493 older than age 70 No difference in overall survival No difference in toxicity No difference in 3rd and 6th cycle dose intensity Sargent, et al. World Congress of GI Cancer, 2005 Results-FOLFOX and Age Measure P/RFS (HR) OS (HR) Advanced Disease RR (OR) Advanced Disease Median dose intensity Oxal (cy 3) Median dose intensity Oxal (cy 6) Median dose intensity 5FU (cy 3) <70 0.7 0.77 >70 0.65 0.82 p-value 0.42 0.79 Toxicity > grade 3 Neurologic Diarrhea <70 14% 11% >70 12% 13% p-value 0.37 0.38 2.56 1.7 0.38 Nausea/vomiting 9% 7% 0.38 100 100 0.89 Any non-heme 35% 38% 0.2 99 99 0.67 Neutropenia 43% 49% 0.04 100 100 0.31 Thrombocytopenia 2% 5% 0.04 Median dose intenstiy 5FU (cy 6) 100 99 0.21 60-day mortality 1.1% 2.3% 0.2% Efficacy by Age PFS/DFS Goldberg, JCO, 2006 Adjuvant Therapy Age related declines in Initiation of adjuvant therapy Age related declines in Completion of adjuvant therapy Dobie, et al JNCI 2006 Adjuvant Therapy Completion Dobie, et al. JNCI 2006 Colon Cancer • Definitive evidence of benefit and tolerance of adjuvant therapy • Older patients are untreated – Less adequate surgery – Lower incidence of chemotherapy – Less chemotherapy received • Leads to lower survival Adjuvant Treatment of Breast Cancer with Chemotherapy Age-Specific SEER Incidence Rates For Breast Cancer SEER 13 Registries for 1998-2002 SEER Data • From 2000-2003, the median age at diagnosis was 61 years of age • Age Distribution – – – – – – 10.6% between 35 and 44 22.1% between 45 and 54 22.8% between 55 and 64 20.4% between 65 and 74 16.8% between 75 and 84 5.4% 85+ years of age. Relative dose-intensity (mean and 95% CI) by age and treatment cycle Lyman, G. H. et al. J Clin Oncol; 21:4524-4531 2003 The International Breast Cancer Study Group Trial VII Percent of patients receiving at least a given percent of protocol-specified CMF dose, according to age group Crivellari, D. et al. J Clin Oncol; 18:1412-1422 2000 Breast Cancer • Evidence of benefit of adjuvant therapylimited data • Older patients are untreated – Lower incidence of chemotherapy – Less chemotherapy received • Leads to lower survival Advanced Ovarian Cancer Ovary: Survival by Age-SEER 55-64 yrs 65-74 yrs >74 yrs Literature Review Author Wimberger Hershman Hershman Petignat Gronlund Pignata Sundararajan Uyar Journal Gyn Onc, 2005 Gyn Onc, 2004 Gyn Onc, 2004 Surg Onc, 2004 Cancer, 2002 CROH, 2004 JCO, 2002 Gyn Onc, 2005 Type retrospective subgroup analysis SEER database; stage II: >65 SEER database Geneva cancer registry Single institution, Denmark review article SEER database single institution review (Cleveland Clinic) Conclusion less optimal surgery Other did not discuss chemotherapy chemotherapy helps >65 years 148 pts less cisplatin less surgery, chemotherapy second line therapy chemotherapy helps >70; 285 pts second line; PS > age 34 pts >65 years less chemotherapy Less surgery/chemo in >80 surgery>age 131 pts Variations in the Use of Chemotherapy for Elderly Patients with Advanced Ovarian Cancer: A Population-Based Study Sundararajan, JCO 2002 Advanced Ovarian Cancer over 65 Years Advanced Ovarian Cancer by Age • No difference: – PFS – OS – Chemotherapy regimens – Chemotherapy dose administered – Chemotherapy toxicity MSKCC-unpublished Ovarian Cancer • Definitive evidence of benefit and tolerance of therapy for advanced disease • Older patients are untreated – Lower incidence of chemotherapy – Less chemotherapy received • Leads to lower survival Malignant Lymphoma Non-Hodgkin’s Lymphoma: SEER Incidence 1973-1975 vs. 1993-1995 Standard-Dose CHOP Yields Comparable Response in Younger and Older NHL Patients All patients 100 80 65 n = 307 P 0.001 100 80 68 60 37 40 64 57 52 Patients on full-dose chemotherapy n = 212 P = 0.12 Patients 60 CR (%) 40 20 0 60 55 20 0 40 40-54 55-64 65 40 40-54 55-64 65 Age (years) Dixon DO, et al. J Clin Oncol 1986;4:295–305. Age (years) International Non-Hodgkin’s Lymphoma (NHL) Prognostic Factors Projects • Age > 60 years • Stage III/IV • Extranodal sites > 2 • PS > 2 • Lactate dehydrogenase (LDH) > normal 5-Year Survival vs Risk Category: <60 Years vs  60 Years 90 80 70 60 50 40 30 20 10 0 83 69 56 44 46 37 <60 years >60 years 32 21 5- Year Survival (%) Low LowIntermediate HighIntermediate High Risk Categories Overall Survival in the Treatment Groups CHOP-R • • • • Cyclophosphamide Adriamycin Vincristine Prednisone days • Rituximab every 21 days for 6-8 cycles 750 mg/m2 50 mg/m2 2 mg 100 mg/m2/day x 5 375 mg/m2 Overall Survival Improved with Rituximab Myeloid Growth Factors: Primary Prophylaxis in Elderly Patients • Patients over 70 years at high risk of early morbidity and mortality Myeloid growth factors reduce risk • Balducci, JCO, 2001 Older patients are at higher risk than younger patients for first-cycle FN 0.50 Cumulative probability of FN  65 years (n = 290) < 65 years (n = 287) 0.40 0.30 0.20 0.10 0.00 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Cycle 1 Days to first FN event Lyman GH, et al. Proc Am Soc Clin Oncol. 2002;21:358a. Abstract 1430. Incidence of Febrile Neutropenia: Primary Prophylaxis Effective p = 0.0043 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% pegfilgrastim (all cycles) 37% Incidence 25% 15% 7% physician discretion (no cycle 1 pegfilgrastim) Cycle 1 Over All cycles aFebrile neutropenia defined as (ANC < 1.0 x 109/L and temperature  38 C on the same day) Conclusion • Society has treated the elderly poorly even when curative therapy exists – Less surgery – Lower use of chemotherapy – Less chemotherapy • • • • Older patients can tolerate standard therapy Under treatment results in lower benefit Need to provide better supportive care Improvements in patient assessment needed Clinical Trials Overcoming Barriers • Focus trial on elderly – Reasonable regimens – Keep it simple • • • • • Relax eligibility: let Doctor/Patient decide Make consent process easier Arrange transportation HCFA to pay for routine care on trial Physician Education Conclusion (I) • Will the patient die of cancer or with cancer? • Will the patient suffer cancer-related morbidity? • What is the effectiveness of the therapy? • Is the patient able to handle the toxicity of treatment? • Will dependency be increased? • What is the goal? Balducci and Beghe, Cancer Control,1999 Conclusion (II) • Elderly specific cancer trials are needed – Avoid subset analysis in which elderly participation is minimal Conclusion (III) • Studies should include (cont): – Some form of geriatric assessment should be performed • • • • • Current standards time consuming New methodology Self-assessment Comorbidity and functional assessment Quality of life evaluation Conclusion (IV) • Studies should emphasize particular aspects of aging, i.e. frailty, vulnerable elderly, well elderly – Functional testing: VES-13 – Predictive laboratory testing – Appropriate endpoints • Survival may not be most important • TTP, QOL, etc. – Pharmacology