Special Populations: Clinical Trials and Elderly Cancer Patients

1. Special Populations:Clinical Trials and Elderly Cancer Patients Stuart M. Lichtman, MD, FACP Associate Attending Memorial Sloan-Kettering Cancer Center

3. Cancer Leading Cause of Death-Jan 05

4. Age Specific Cancer Incidence Rates

5. Cancer Mortality and Mortality Rates

6. Incidence of 10 Major Cancers in Patients Over 65 years (�73-�95)

7. % US Population 65 and older

8. Life Expectancy: Woman

9. Life Expectancy: Woman

10. Life Expectancy: Woman

11. 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

12. Therefore� More older patients Living longer Living healthier More indications for anticancer therapy Many more patients in need of getting more therapy

13. 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

20. 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

21. Elderly and Registration Trials

22. Elderly and Registration Trials

23. NCI Sponsored Trials by Age

24. NCI Sponsored Trials

25. Topics Pharmacology Design Issues Clinical Trials Reporting

26. Pharmacology Absorption Distribution Metabolism Excretion

27. 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

28. 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 t�

29. 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

30. Medications

31. 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

32. Chemotherapy P450 Metabolism

33. 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

34. 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)

35. Sample CrCl Calculations Cockcroft-Gault: Female

36. Sample CrCl Calculations Using Cockcroft-Gault:Female

37. 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

38. 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

39. Influence of pharmacokinetics

40. Pharmacodynamic Heterogeneity of Effect Tremendous variability in toxicity Increased susceptibility Myelosuppression Mucositis Cardiac toxicity Nervous system toxicity

41. Design Issues

42. Design Issues Patient Selection Endpoints Dose Limiting Toxicity Toxicity Evaluation

43. Patient Selection Which older patient? Comorbidity Endorgan dysfunction: renal, hepatic Cardiac disease Neuropathy Prior malignancy, i.e. prior chemotherapy, radiotherapy

44. Which Older Patient?: Stages of Aging

45. Patient Selection: Stages of Aging

46. 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?

47. 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

48. Design Issues: DLT Hematologic Modulated by growth factors Nonhematologic Predominating Are our toxicity scales adequate for older patients? Function

49. Non-hematologic

50. Toxicity Evaluation-CTC v2

51. Toxicity Evaluation: Functional

52. Toxicity Evaluation-Frail

53. 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

54. Functional Assessment as Endpoint Alterations in: ADL IADL Geriatric syndromes Falls, delirium, incontinence, nutrition Maintain independence/avoid further dependence

55. Comprehensive Geriatric Assessment Is Highly Sensitive to Common Problems in Elderly There is a high prevalence of problems that could adversely affect course of cancer and its treatment; the CGA is the best tool for detecting such problems. Findings in 200 consecutive elderly patients (age =70) at H. Lee Moffitt Cancer Center and Research Institute, screened by CGA:1 18% dependent in ADL (dressing, eating, use of toilet, etc) 72% dependent in IADL (driving, shopping, meal preparation, etc) 36% with serious comorbidity on Charlson scale (short list of selected diseases) 94% with serious comorbidity on CIRS-G scale (Cumulative Illness Rating Scale-Geriatric; comprehensive listing of diseases) 22% with memory disorder 19% with poor nutritional status 41% with polypharmacy Conclusions: High prevalence of problems in elderly patients CGA is highly sensitive in revealing these problems CGA is indicated in all patients age =70 (or younger if signs of aging are present, such as falls, memory loss, loss of independence) � Balducci L, Extermann M. Management of cancer in the older patient: a practical approach. Oncologist. 2000;5:224�237. There is a high prevalence of problems that could adversely affect course of cancer and its treatment; the CGA is the best tool for detecting such problems. Findings in 200 consecutive elderly patients (age =70) at H. Lee Moffitt Cancer Center and Research Institute, screened by CGA:1 18% dependent in ADL (dressing, eating, use of toilet, etc) 72% dependent in IADL (driving, shopping, meal preparation, etc) 36% with serious comorbidity on Charlson scale (short list of selected diseases) 94% with serious comorbidity on CIRS-G scale (Cumulative Illness Rating Scale-Geriatric; comprehensive listing of diseases) 22% with memory disorder 19% with poor nutritional status 41% with polypharmacy Conclusions: High prevalence of problems in elderly patients CGA is highly sensitive in revealing these problems CGA is indicated in all patients age =70 (or younger if signs of aging are present, such as falls, memory loss, loss of independence) � Balducci L, Extermann M. Management of cancer in the older patient: a practical approach. Oncologist. 2000;5:224�237.

56. Comprehensive Geriatric Assessment Is Highly Sensitive to Common Problems in Elderly There is a high prevalence of problems that could adversely affect course of cancer and its treatment; the CGA is the best tool for detecting such problems. Findings in 200 consecutive elderly patients (age =70) at H. Lee Moffitt Cancer Center and Research Institute, screened by CGA:1 18% dependent in ADL (dressing, eating, use of toilet, etc) 72% dependent in IADL (driving, shopping, meal preparation, etc) 36% with serious comorbidity on Charlson scale (short list of selected diseases) 94% with serious comorbidity on CIRS-G scale (Cumulative Illness Rating Scale-Geriatric; comprehensive listing of diseases) 22% with memory disorder 19% with poor nutritional status 41% with polypharmacy Conclusions: High prevalence of problems in elderly patients CGA is highly sensitive in revealing these problems CGA is indicated in all patients age =70 (or younger if signs of aging are present, such as falls, memory loss, loss of independence) � Balducci L, Extermann M. Management of cancer in the older patient: a practical approach. Oncologist. 2000;5:224�237. There is a high prevalence of problems that could adversely affect course of cancer and its treatment; the CGA is the best tool for detecting such problems. Findings in 200 consecutive elderly patients (age =70) at H. Lee Moffitt Cancer Center and Research Institute, screened by CGA:1 18% dependent in ADL (dressing, eating, use of toilet, etc) 72% dependent in IADL (driving, shopping, meal preparation, etc) 36% with serious comorbidity on Charlson scale (short list of selected diseases) 94% with serious comorbidity on CIRS-G scale (Cumulative Illness Rating Scale-Geriatric; comprehensive listing of diseases) 22% with memory disorder 19% with poor nutritional status 41% with polypharmacy Conclusions: High prevalence of problems in elderly patients CGA is highly sensitive in revealing these problems CGA is indicated in all patients age =70 (or younger if signs of aging are present, such as falls, memory loss, loss of independence) � Balducci L, Extermann M. Management of cancer in the older patient: a practical approach. Oncologist. 2000;5:224�237.

57. 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

58. 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.

59. 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.

60. 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 (28-29), 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

61. Publications in Geriatric Oncology

62. 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

63. 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).

64. Data

65. 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

66. 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;

67. 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

68. Thank You

69. Supplemental Slides

70. Comorbidity is Key Factor

71. Burden of ComorbidityYancik Variety of comorbidities hypertension heart disease arthritis gastrointestinal problems anemia eye problems urinary tract problems previous cancers gall bladder problems COPD diabetes thyroid/glandular

72. Burden of ComorbidityYancik Patients with >5 comorbid conditions 55-65 years 13% 66-74 years 24% 75+ years 39%

73. Burden of ComorbidityYancik Predictors of early mortality (24 months) with colon cancer Disorder RR heart disease 1.31 COPD 1.51 renal failure 1.73 liver disease 2.54

74. Effect of Comorbidity of 3 Year Survival with Breast CancerMortality v. Comorbidity

75. Geriatric Syndromes Delirium Dementia Incontinence Falls Pressure ulcers Malnutrition Osteoporosis Language Hearing and vision Sleep

76. Activities of Daily Living (ADL) Toilet Feeding Dressing Grooming Ambulation Bathing

77. Instrumental ADL (IADL) Telephone Shopping Food preparation Housekeeping Laundry Transportation Medication

78. 8% if fully independent, 14% if dependent in IADL, 27% if dependent in ADL, ? 40% if institutionalized. Reuben Am J Med 1992;93:663 2-year mortality rate for persons aged 70 years and older D: D:

79. Frailty Age =85 3+ comorbidity 1+ geriatric syndrome(s) 1+ ADL Biologic markers: d-dimer, IL-6

80. Survival by Functioning

81. Guidelines for Management of theOlder Cancer Patient: The Assessment Function Comorbidity Cognition Nutrition Pharmacy Socioeconomic status Geriatric syndromes

82. Aging Physiology and Cancer

83. 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

85. This slide demonstrates the change in clearance by age.This slide demonstrates the change in clearance by age.

86. 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)

87. Creatinine Clearance and Aging

88. Cockcroft-Gault formula

89. Sample CrCl Calculations Cockcroft-Gault: Female

90. Sample CrCl Calculations Using Cockcroft-Gault:Female

91. Renal DysfunctionNational Kidney Foundation

92. 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.

93. 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.

94. Are elderly cancer patients under treated? Stuart M. Lichtman, MD Memorial Sloan-Kettering Cancer Center

95. What is under treatment? Poor evaluation? Poor treatment? Surgery Radiation Chemotherapy

96. Under treatment Question needs to be answered in terms of: Goal of therapy Potential benefit of therapy-what is the best possible outcome?

97. Goal Palliative No potential for cure Curative therapy exists Patient cannot tolerate potentially curable therapy Who decides How is this decided �self fulfilling prophesy�

98. Curative therapy Adjuvant breast Adjuvant colon Advanced ovarian cancer Large cell lymphoma

99. Adjuvant Treatment of Colon Cancer

100. 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.

101. Age-Specific SEER Incidence Rates by Sex for Colon and Rectum Cancer, 1998-2002

102. Questions being asked Do older patients receive adjuvant chemotherapy? Do older patients benefit from adjuvant therapy?

103. Age and Adjuvant Chemotherapy Use After Surgery forStage III Colon Cancer

104. Questions being asked Do older patients receive adjuvant chemotherapy? Do older patients benefit from adjuvant therapy?

106. Colon Cancer-AdjuvantAge NOT A Factor

107. Phase III MOSAIC Trial:Adjuvant Oxaliplatin This large, multicenter, multinational phase III study (de Gramont, et al) aimed to demonstrate a 25% decrease in the risk of recurrence at 3 years for patients receiving FOLFOX in stage II/III colon cancer. Since 1998, 2248 patients with completely resected stage II (40%) or III (60%) colorectal cancer were randomly assigned to receive LV5FU2 (leucovorin, fluorouracil, bolus and infusion), also known as the de Gramont schedule, or FOLFOX (LV5FU2 + oxaliplatin) bimonthly for 12 cycles. At the onset of the study, the expected 3-year disease free survival was assumed to be 73% in the control arm and 79% in the treatment arm. This large, multicenter, multinational phase III study (de Gramont, et al) aimed to demonstrate a 25% decrease in the risk of recurrence at 3 years for patients receiving FOLFOX in stage II/III colon cancer. Since 1998, 2248 patients with completely resected stage II (40%) or III (60%) colorectal cancer were randomly assigned to receive LV5FU2 (leucovorin, fluorouracil, bolus and infusion), also known as the de Gramont schedule, or FOLFOX (LV5FU2 + oxaliplatin) bimonthly for 12 cycles. At the onset of the study, the expected 3-year disease free survival was assumed to be 73% in the control arm and 79% in the treatment arm.

110. 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

111. Results-FOLFOX and Age

112. Efficacy by Age PFS/DFS

113. Adjuvant Therapy

114. Adjuvant Therapy Completion

115. 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

116. Adjuvant Treatment of Breast Cancer with Chemotherapy

117. Age-Specific SEER Incidence Rates For Breast CancerSEER 13 Registries for 1998-2002

118. 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.

123. Breast Cancer Evidence of benefit of adjuvant therapy-limited data Older patients are untreated Lower incidence of chemotherapy Less chemotherapy received Leads to lower survival

124. Advanced Ovarian Cancer

125. Ovary: Survival by Age-SEER

126. Literature Review

127. Variations in the Use of Chemotherapy for Elderly Patientswith Advanced Ovarian Cancer: A Population-Based Study

129. Advanced Ovarian Cancer over 65 Years

130. Advanced Ovarian Cancer by Age No difference: PFS OS Chemotherapy regimens Chemotherapy dose administered Chemotherapy toxicity

131. 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

132. Malignant Lymphoma

133. Non-Hodgkin�s Lymphoma: SEER Incidence 1973-1975 vs. 1993-1995 The SEER data shows that the incidence of non-Hodgkin�s lymphoma rises with age. The recent database also indicates that the overall incidence of non-Hodgkin�s lymphoma has increased over the indicated twenty year period. The exact cause remains unknown. Speculation includes the AIDS epidemic, environmental factors and our increased ability to make specific diagnoses and an increased aggressiveness in pursing diagnoses in older patients. Reference Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK (eds). SEER Cancer Statistics Review, 1973-1998, National Cancer Institute. Bethesda, MD, 2001. http://seer.cancer.gov/Publications/CSR1973_1998/The SEER data shows that the incidence of non-Hodgkin�s lymphoma rises with age. The recent database also indicates that the overall incidence of non-Hodgkin�s lymphoma has increased over the indicated twenty year period. The exact cause remains unknown. Speculation includes the AIDS epidemic, environmental factors and our increased ability to make specific diagnoses and an increased aggressiveness in pursing diagnoses in older patients. Reference Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK (eds). SEER Cancer Statistics Review, 1973-1998, National Cancer Institute. Bethesda, MD, 2001. http://seer.cancer.gov/Publications/CSR1973_1998/

134. Standard-Dose CHOP Yields Comparable Response in Younger and Older NHL Patients On standard-dose CHOP regimen, older and younger lymphoma patients showed similar frequency and duration of complete response, and frequency of toxicity. Classic study from Southwest Oncology Group:1 307 patients with advanced diffuse histiocytic lymphoma (a form of non-Hodgkin�s lymphoma). Treatment: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), with or without bleomycin, and with or without immunotherapy. Population included 81 patients age 65 or over, in whom protocol ordered automatic 50% reduction in chemotherapy dosage: 58 received half-dose treatment (as per protocol) 23 received full-dose treatment (in violation of protocol) For all patients (N = 307), complete response rate declined with age (P <0.001). However, in patients who received full-dose chemotherapy (n = 212), no significant age-related differences in: Complete response rate Duration of complete response (relative relapse rate) Frequency of treatment-related complications Conclusion: automatic reduction in chemotherapy dosage based on age contributed to poorer outcome in older patients. Findings consistent with later research suggesting that older patients with aggressive non-Hodgkin�s lymphoma derive benefit from treatment comparable to that achieved in younger patients2 and should be treated with the intent of achieving cure.3 Dixon DO, Neilan B, Jones SE, et al. Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol. 1986;4:295-305. Gaynor ER, Dahlberg S, Fisher RI. Factors affecting reduced survival of the elderly with intermediate and high-grade lymphoma: an analysis of SWOG-8516 (int 0067)�the National High Priority Lymphoma Study: a randomized comparison of CHOP vs m-BACOD vs ProMACE-CytaBOM vs MACOP-B. Proc ASCO. 1994;13. Abstract 1250. Tirelli U, Zagonel V, Errante D, et al. Treatment of non-Hodgkin�s lymphoma in the elderly: an update. Hematol Oncol. 1998;16:1�13. On standard-dose CHOP regimen, older and younger lymphoma patients showed similar frequency and duration of complete response, and frequency of toxicity. Classic study from Southwest Oncology Group:1 307 patients with advanced diffuse histiocytic lymphoma (a form of non-Hodgkin�s lymphoma). Treatment: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), with or without bleomycin, and with or without immunotherapy. Population included 81 patients age 65 or over, in whom protocol ordered automatic 50% reduction in chemotherapy dosage: 58 received half-dose treatment (as per protocol) 23 received full-dose treatment (in violation of protocol) For all patients (N = 307), complete response rate declined with age (P <0.001). However, in patients who received full-dose chemotherapy (n = 212), no significant age-related differences in: Complete response rate Duration of complete response (relative relapse rate) Frequency of treatment-related complications Conclusion: automatic reduction in chemotherapy dosage based on age contributed to poorer outcome in older patients. Findings consistent with later research suggesting that older patients with aggressive non-Hodgkin�s lymphoma derive benefit from treatment comparable to that achieved in younger patients2 and should be treated with the intent of achieving cure.3 Dixon DO, Neilan B, Jones SE, et al. Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol. 1986;4:295-305. Gaynor ER, Dahlberg S, Fisher RI. Factors affecting reduced survival of the elderly with intermediate and high-grade lymphoma: an analysis of SWOG-8516 (int 0067)�the National High Priority Lymphoma Study: a randomized comparison of CHOP vs m-BACOD vs ProMACE-CytaBOM vs MACOP-B. Proc ASCO. 1994;13. Abstract 1250. Tirelli U, Zagonel V, Errante D, et al. Treatment of non-Hodgkin�s lymphoma in the elderly: an update. Hematol Oncol. 1998;16:1�13.

135. International Non-Hodgkin�s Lymphoma (NHL) Prognostic Factors Projects Age > 60 years Stage III/IV Extranodal sites > 2 PS > 2 Lactate dehydrogenase (LDH) > normal This prognostic factor was based on adults with aggressive non-Hodgkin's lymphoma from 16 institutions and cooperative groups in the United States, Europe, and Canada who were treated between 1982 and 1987 with combination-chemotherapy regimens containing doxorubicin were evaluated for clinical features predictive of overall survival and relapse-free survival. Features that remained independently significant in step-down regression analyses of survival were incorporated into models that identified groups of patients of all ages and groups of patients no more than 60 years old with different risks of death. In 2031 patients of all ages, the model, based on age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites, identified four risk groups with predicted five-year survival rates of 73 percent, 51 percent, 43 percent, and 26 percent. In 1274 patients 60 or younger, an age-adjusted model based on tumor stage, lactate dehydrogenase level, and performance status identified four risk groups with predicted five-year survival rates of 83 percent, 69 percent, 46 percent, and 32 percent. In both models, the increased risk of death was due to both a lower rate of complete responses and a higher rate of relapse from complete response. These two indexes, called the international index and the age-adjusted international index, were significantly more accurate than the Ann Arbor classification in predicting long-term survival. Reference: A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994. This prognostic factor was based on adults with aggressive non-Hodgkin's lymphoma from 16 institutions and cooperative groups in the United States, Europe, and Canada who were treated between 1982 and 1987 with combination-chemotherapy regimens containing doxorubicin were evaluated for clinical features predictive of overall survival and relapse-free survival. Features that remained independently significant in step-down regression analyses of survival were incorporated into models that identified groups of patients of all ages and groups of patients no more than 60 years old with different risks of death. In 2031 patients of all ages, the model, based on age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites, identified four risk groups with predicted five-year survival rates of 73 percent, 51 percent, 43 percent, and 26 percent. In 1274 patients 60 or younger, an age-adjusted model based on tumor stage, lactate dehydrogenase level, and performance status identified four risk groups with predicted five-year survival rates of 83 percent, 69 percent, 46 percent, and 32 percent. In both models, the increased risk of death was due to both a lower rate of complete responses and a higher rate of relapse from complete response. These two indexes, called the international index and the age-adjusted international index, were significantly more accurate than the Ann Arbor classification in predicting long-term survival. Reference: A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994.

136. 5-Year Survival vs Risk Category: <60 Years vs ? 60 Years Risk categories in terms of number of factors present: Low-0,1; Low-Intermediate-2; High-Intermediate-3, High 4,5. The table shows that there is a significant change in 5 year survival by risk category and age. It clearly demonstrates that prognosis for non-Hodgkin�s lymphoma in the older patient population can bary from 56% to 21% depending category.Risk categories in terms of number of factors present: Low-0,1; Low-Intermediate-2; High-Intermediate-3, High 4,5. The table shows that there is a significant change in 5 year survival by risk category and age. It clearly demonstrates that prognosis for non-Hodgkin�s lymphoma in the older patient population can bary from 56% to 21% depending category.

137. Overall Survival in the Treatment Groups The curve shows that overall survival did not vary by treatment regimen.The curve shows that overall survival did not vary by treatment regimen.

138. CHOP-R Cyclophosphamide 750 mg/m2 Adriamycin 50 mg/m2 Vincristine 2 mg Prednisone 100 mg/m2/day x 5 days Rituximab 375 mg/m2 every 21 days for 6-8 cycles

139. Overall Survival Improved with Rituximab

140. 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 It is suggested that patients aged 70 and older who are receiving moderately toxic chemotherapy (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone [CHOP] or CHOP-like) be specifically mentioned as a special high-risk group recommended to receive primary prophylactic treatment with growth factors starting up front with the first course of chemotherapy. The suggestion is based on the following considerations and data. In nine studies of older individuals with large-cell non-Hodgkin�s lymphoma, the risk of life-threatening neutropenia was higher than 40% in all studies. The risk of neutropenic infections varied between 21% and 47%, and the risk of infectious death varied between 5% and 30%. The majority of deaths and serious infections occurred in the first course of chemotherapy, before secondary prophylaxis with growth factors could even be considered. In the study of Gomez et al, there were 51 deaths (20%) among 260 patients receiving chemotherapy; 36 deaths occurred during the first two courses of chemotherapy, and 63% of these were after the first course. Generally the seriousness of neutropenic infections is increased, and so is the duration of hospitalization in older individuals, involving a substantially increased cost per infection. Furthermore, hospitalization of older individuals is associated with increased risk of functional dependence that may increase the cost of treatment due to expensive home care and rehabilitation. In at least four studies, hematopoietic growth factors reduced the risk of neutropenia and neutropenic infection by 32% to 83% in older patients with large-cell non-Hodgkin�s lymphomas. The National Comprehensive Cancer Network advisory panel for the guidelines for the management of older individuals has unanimously recommended that hematopoietic growth factors be used routinely in persons aged 70 and older who are receiving moderately toxic chemotherapy. References Balducci L, Lyman GH. Patients aged > or = 70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol. 2001;19:1583-1585. Gomez H, Hidalgo M, Casanova L, et al. Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin's lymphoma: results of a multivariate analysis. J Clin Oncol. 1998;16:2065-2069. It is suggested that patients aged 70 and older who are receiving moderately toxic chemotherapy (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone [CHOP] or CHOP-like) be specifically mentioned as a special high-risk group recommended to receive primary prophylactic treatment with growth factors starting up front with the first course of chemotherapy. The suggestion is based on the following considerations and data. In nine studies of older individuals with large-cell non-Hodgkin�s lymphoma, the risk of life-threatening neutropenia was higher than 40% in all studies. The risk of neutropenic infections varied between 21% and 47%, and the risk of infectious death varied between 5% and 30%. The majority of deaths and serious infections occurred in the first course of chemotherapy, before secondary prophylaxis with growth factors could even be considered. In the study of Gomez et al, there were 51 deaths (20%) among 260 patients receiving chemotherapy; 36 deaths occurred during the first two courses of chemotherapy, and 63% of these were after the first course. Generally the seriousness of neutropenic infections is increased, and so is the duration of hospitalization in older individuals, involving a substantially increased cost per infection. Furthermore, hospitalization of older individuals is associated with increased risk of functional dependence that may increase the cost of treatment due to expensive home care and rehabilitation. In at least four studies, hematopoietic growth factors reduced the risk of neutropenia and neutropenic infection by 32% to 83% in older patients with large-cell non-Hodgkin�s lymphomas. The National Comprehensive Cancer Network advisory panel for the guidelines for the management of older individuals has unanimously recommended that hematopoietic growth factors be used routinely in persons aged 70 and older who are receiving moderately toxic chemotherapy. References Balducci L, Lyman GH. Patients aged > or = 70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol. 2001;19:1583-1585. Gomez H, Hidalgo M, Casanova L, et al. Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin's lymphoma: results of a multivariate analysis. J Clin Oncol. 1998;16:2065-2069.

141. Older patients are at higher risk than younger patients for first-cycle FN Key Point: Elderly patients are at a higher risk for FN in the first chemotherapy cycle than younger patients. Background: Lyman et al conducted a retrospective analysis of data from 577 patients with NHL who were treated with CHOP at 1 of 12 community or academic oncology practices between 1991 and 1999. Twenty-eight percent of all patients in the analysis experienced an FN event. Patients age ? 65 years represented 50% of all patients, but accounted for 62% of FN events. Older patients with NHL had a greater risk of FN, even after adjustment for dose intensity and comorbidities. The time to the first FN event was shorter in patients aged 65 years or older (P = 0.0002). Lyman GH, Morrison VA, Dale DC, et al. Risk of first febrile neutropenia among patients receiving CHOP chemotherapy. Proc Am Soc Clin Oncol. 2002;21:358a. Abstract 1430.Key Point: Elderly patients are at a higher risk for FN in the first chemotherapy cycle than younger patients. Background: Lyman et al conducted a retrospective analysis of data from 577 patients with NHL who were treated with CHOP at 1 of 12 community or academic oncology practices between 1991 and 1999. Twenty-eight percent of all patients in the analysis experienced an FN event. Patients age ? 65 years represented 50% of all patients, but accounted for 62% of FN events. Older patients with NHL had a greater risk of FN, even after adjustment for dose intensity and comorbidities. The time to the first FN event was shorter in patients aged 65 years or older (P = 0.0002). Lyman GH, Morrison VA, Dale DC, et al. Risk of first febrile neutropenia among patients receiving CHOP chemotherapy. Proc Am Soc Clin Oncol. 2002;21:358a. Abstract 1430.

142. Incidence of Febrile Neutropenia: Primary Prophylaxis Effective The p-value for the incidence of FN in cycle 1 is significant and is 0.006. Primary Endpoint Over all cycles, the percentage of patients experiencing febrile neutropenia was statistically significantly lower for patients receiving pegfilgrastim in all cycles compared with patients receiving no pegfilgrastim in cycle 1 The p-value for the incidence of FN in cycle 1 is significant and is 0.006. Primary Endpoint Over all cycles, the percentage of patients experiencing febrile neutropenia was statistically significantly lower for patients receiving pegfilgrastim in all cycles compared with patients receiving no pegfilgrastim in cycle 1

143. 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

144. Clinical Trials

145. 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

146. 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?

147. Conclusion (II) Elderly specific cancer trials are needed Avoid subset analysis in which elderly participation is minimal

148. 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

149. 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