How Old is Too Old for Chemotherapy in Early C olon Colon Cancer: Role of Geriatric Assessments Winson Y. Cheung, MD, MPH, FRCPC

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1 How Old is Too Old for Chemotherapy in Early Colon Cancer: Role of Geriatric Assessments Winson Y. Cheung, MD, MPH, FRCPC British Columbia Cancer Agency - Vancouver CAGPO - October 20,

2 About Me Born and raised in Vancouver Trained in Vancouver, Winnipeg, Toronto, Boston There really is no t in my name Clinical focus is medical oncology Academic focus is outcomes research with specific interest in health care disparities (e.g. age, ethnicity, urban/rural residence ) Design and use of databases and surveys 2

3 Objectives To describe potential assessment tools in geriatric oncology To present data from the BC Cancer Agency that explores treatment patterns in older patients with early colon cancer To review some recent analyses of the benefit of chemotherapy in elderly patients with early and advanced stage colon cancer 3

4 Epidemiology 3rd most common cancer and 2nd most common cause of cancer deaths In Canada: 21,500 incident cases per year 9,000 deaths per year Median age at diagnosis is 72 years 24% age % age % age 85 4

5 Incidence by Age 5

6 Life Expectancy by Age 6

7 Why Discuss the Elderly? The population is getting older Many elderly patients remain active and functional Some have good and reasonable life expectancy Improved tolerance to systemic therapy Better supportive care strategies More appropriate and coordinated follow-up Increased familiarity with systemic therapy regimens and dose modifications 7

8 Why Discuss the Elderly? Underrepresentation of elderly in clinical trials Less than 15% to 20% >/= 70 years old How to extrapolate to routine clinical practice? Inconsistencies without standard guidelines Different definitions of elderly or extremely old Inter- and intra-variability in practice Aging is a highly variable phenomenon 8

9 Aging is Highly Variable Diseases Diet Environment Genes Activity Optimal Usual Pathological 9

10 Aging is Highly Variable 10

11 Geriatric Assessment Tools 11

12 Geriatric Assessment Tools Performance Status Karnofsky ECOG ADLs and IADLs Comprehensive Geriatric Assessment 12

13 Geriatric Assessment Tools Useful for the assessment of: General tolerance to chemo Short-term cancer prognosis However, performance status tends to underestimate actual degree of functional impairment in older patients Discordant patient vs. physician ratings; subject to bias 13

14 Geriatric Assessment Tools ADLs (necessary for basic living) feeding, grooming, transferring, and toileting IADLs (necessary for independent living) shopping, managing finances, housekeeping, preparing meals, and ability to take medications Less robust correlations with cancer outcomes 14

15 Geriatric Assessment Tools 15

16 Who Needs a CGA? NCCN and ISGO guidelines: recommend the routine use of a comprehensive geriatric assessment for the older patient with cancer (defined as age 65 years or older) to facilitate physicians in developing a coordinated plan for cancer treatment and guiding g appropriate p interventions for specific problems 16

17 CGA: Pros Predicts complications and side effects from cancer treatments Estimates short-term and possibly long-term cancer prognosis Assists in cancer treatment decisions Detects problems not found by routine history and physical examination Improves mental health and wellbeing Contributes to better cancer pain control 17

18 CGA: Cons TIME CONSUMING! 1 hour (or more!) Potential solutions: a) Mailed CGA b) Self-administered CGA c) Clinical interview d) Tools to screen at risk patients e.g. G8 e) Simplified CGA e.g. VES-13 18

19 G8 Scale Screening Tool A B Items Loss of appetite. Has food intake declined over the past 3 months due to loss of appetite, digestive problems, chewing or swallowing difficulties? Loss of weight during the last months Results 0: severe anorexia; 1: moderate anorexia; 2: no anorexia 0: weight loss >3 kg (6.6 lbs); 1: does not know; 2: weight loss between 1 and 3 kg; 3: no weight loss C E Mobility Neuropsychological problems 0: bed or chair bound; 1: able to get out of bed/chair but not to go out; 2: goes out 0: severe dementia or depression; 1: moderate dementia or depression; 2: no psychological problem F H P Body Mass Index Takes > 3 prescription drugs per day In comparison with other people of the same age, how do they consider their health status 0: BMI <18.5; 1: BMI between 18.5 and <21; 2: BMI 21 to <23; 3: BMI 23 0: yes; 1: no 0: not as good; 1: does not know; 2: as good; 3: better Age 0: >85; 1: 80-85; 2: <80 Total score /18 19

20 VES-13 Simplified CGA Score >/=5 suggests vulnerable elderly patient 20

21 CGA: Cons Lack of standardization There is no uniform CGA measurement tool All include some form of multidisciplinary assessment of the following domains: physical function, co-morbid conditions, psychological state, social support, cognitive function, nutrition, and poly-pharmacy p y CGA requires multidisciplinary participation from the outset (in contrast to ECOG) 21

22 How to Use CGA Results? 22

23 How to Use CGA Results? 23

24 Predicting Toxicity Low hemoglobin Poor renal function Falls in preceding 6 months Etc 24

25 Predicting Toxicity 25

26 Analyses of the Elderly 26

27 Elderly ACCENT Sargent DJ, et al. NEJM 2001 Pooled analysis of 7 trials: 5-FU/LV vs. surgery alone N=3,351 Patients were grouped into 2 age categories: </=70 vs. >70 years In addition to outcomes, toxic effects were measured: nausea or vomiting, diarrhea, stomatitis, and leukopenia 27

28 Elderly ACCENT Patients were also subsequently grouped into 4 age categories ( 50, 51 to 60, 61 to 70, and >70 years old) Adjuvant treatment was associated with: 24% reduction in mortality (HR 0.76) across all ages 32% reduction in disease recurrence (HR 0.68) across all ages There was a higher rate of grade 3 or 4 neutropenia in the oldest age group (8 vs. 4%) 28

29 Elderly ACCENT Selected elderly patients with colon cancer can receive the same benefit from fluorouracil-based adjuvant therapy as their younger counterparts Pooled clinical trial data: Selection bias Presumably fit elderly patients were enrolled onto the individual clinical trials Less than 1% of the trial participants were in their 80s Only 15% were in their 70s 29

30 Elderly Population-Based SEER, Medicare, National Cancer Database (all US) Findings indicate that the benefits of adjuvant 5-FU and oxaliplatin-based chemotherapy are evident in older adults However Chemotherapy was used less often in the elderly population (>80% in young; <40% in older) Magnitude of benefit declined with advancing age Older patients are more prepared to stop systemic therapy at the first sign of toxicities 30

31 MOSAIC Revisited Subgroup analysis based on: Elderly colon cancer patients aged 70 to 75 years Conclusions - HR comparing FOLFOX4 vs. 5-FU: 0.93 (95% CI, 0.64 to 1.35) for DFS 0.72 (95% CI, 0.47 to 1.11) for TTR 1.10 (95% CI, 0.73 to 1.65) for OS Limitations: Very few elderly patients treated with FOLFOX Results conflict with similar analyses involving capecitabine, 5-FU, and oxaliplatin 31

32 What Happens at the What Happens at the BC Cancer Agency? 32

33 What Happens at BCCA? Ko J, Cheung W, et al, on behalf of GICOU Adjuvant Chemotherapy Initiation and Early Treatment Discontinuation in Elderly Patients with Stage III Colon Cancer Elderly defined as >/= 70 years None vs. Capecitabine vs. FOLFOX Main impetus: Research suggests that elderly patients with cancer are commonly undertreated, but the precise reasons for this age disparity are unclear 33

34 BCCA Experience Study Objectives 1. To evaluate the impact of advanced age (< vs. >/=70) on choice of adjuvant chemotherapy in stage III colon cancer 2. To determine the reasons for selecting a specific adjuvant treatment option (none vs. capecitabine vs. FOLFOX) 3. To examine whether the treatment effect on outcomes is modified by advanced age 34

35 BCCA Experience Study Cohort A review of 810 patients who were diagnosed with stage III colon cancer in BC from 2006 to 2008, and evaluated at one of the BCCA centres. Statistical Considerations Multivariate Cox regression models were constructed to evaluate the associations of age and adjuvant chemotherapy chosen with colon cancer-specific survival in young vs. old. 35

36 Results Baseline Characteristics Variable Group All Cases (N=810) <70 (N=423) >/=70 (N=387) P-value Sex Female 48% 49% 47% Male 52% 51% 53% Chemo None 26% 9% 43% <.0001 (Y/N) Yes 74% 91% 57% Regimen Single Agent 41% 25% 68% <.0001 Combination 59% 74% 32% Regimen Unknown 1% 1% 0% 36

37 Results Reasons for No Chemotherapy by Age Group 37

38 Results Reasons for Single vs. Combination by Age 38

39 Results Reasons for Delays / Reductions by Age Group 39

40 Results Reasons for Discontinuations by Age Group 40

41 Results Cox Proportional Hazards Model on CSS Lymphovascular Invasion vs. None Distal vs. Proximal Tumor T3 vs. T1/2 T4 vs. T1/2 N2 vs. N1 >/=70 vs. <70 (untreated) >/=70 vs. <70 (treated) Cape vs. None (<70) Cape vs. None (>/=70) FOLFOX vs. None (<70) FOLFOX vs. None (>/=70) HR

42 Conclusions 1. To evaluate the impact of advanced age (< vs. >/=70) on choice of adjuvant chemotherapy in stage III colon cancer There is a statistically significant difference in adjuvant chemotherapy choice based on age Preference for combination in <70 (74%) Preference for single agent in >/=70 (68%) P<

43 Conclusions 2. To determine the reasons for selecting a specific adjuvant treatment option (none vs. capecitabine vs. FOLFOX) For the young subset, patient choice and delay in treatment initiation are the main reasons for not offering chemotherapy For the elderly subset, patient age, comorbidities, and y, p g,, the perception that the chemotherapy may be of minimal benefit are the main reasons for not offering chemotherapy 43

44 Conclusions 2. To determine the reasons for selecting a specific adjuvant treatment option (none vs. capecitabine vs. FOLFOX) Reasons for providing capecitabine rather than FOLFOX are mostly similar in both age groups One exception: patient age alone is a major reason why some patients received capecitabine rather than FOLFOX in the elderly, but not in the young 44

45 Conclusions 2. To determine the reasons for selecting a specific adjuvant treatment option (none vs. capecitabine vs. FOLFOX) Once on chemotherapy, both young and older patients experienced similar rates of treatment discontinuations and dose delays and/or reductions Most common reason for early stopping was side y pp g effects; this was statistically similar in both age groups 45

46 Conclusions 3. To examine whether the treatment effect on outcomes is modified by advanced age Age alone did not predict for (worse) cancer-specific survival in stage III colon cancer, with or without chemotherapy Both monotherapy and combination regimens appear to have a favorable impact on cancer-specific survival in the young and the elderly groups Interaction p (age and treatment) = non-significant 46

47 Summary Overall Conclusion: It appears adjuvant chemotherapy should not be withheld from colon cancer patients based on advanced age alone if carefully selected One must consider physiological or functional age rather than chronological age 47

48 What About Stage II What About Stage II Colon Cancer? 48

49 Stage II Benefits of adjuvant chemotherapy is uncertain in stage II colon cancer Meta-analyses show non-significant trend towards potential benefit Up to 1/3 rd of patients with stage II colon cancer receive adjuvant chemotherapy US Medicare beneficiaries Treatment is typically offered to patients who are considered high risk 49

50 Stage II Considered high risk if one or more of the following features is present: T4 stage Poorly differentiated histology Bowel obstruction or perforation <12 Lymph nodes resected Lymphovascular invasion Perineural invasioni Close margins Elevated preoperative CEA 50

51 Stage II Consistent, significant improvements in RFS, DSS, and OS were only observed in T4 stage: 0.63 (95% CI, 0.42 to 0.95) for RFS 0.59 (95% CI, 0.37 to 0.93) for DSS 0.50 (95% CI, 0.33 to 0.77) for OS Are these treatment benefits similarly observed in elderly l patients t (defined d as >/=70 years)? P interaction for all 3 endpoints = NS 51

52 What About Metastatic CRC? 52

53 Bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer (mcrc): Results of a randomized d international ti phase III trial (AVEX) David Cunningham, 1 Istvan Lang, 2 Eugenio Marcuello, 3 Vito Lorusso, 4 Janja Ocvirk, 5 Dong Bok Shin, 6 Derek Jonker, 7 Stuart Osborne, 8 Niko Andre, 9 Daniel Waterkamp, 8 Mark P. Saunders 10 1 Royal Marsden Hospital, London and Surrey, United Kingdom; 2 National Institute of Oncology, Budapest, Hungary; 3 Hospital de Sant Pau de Barcelona, Barcelona, Spain; 4 National Cancer Institute "Giovanni Paolo II" Bari, Italy; 5 Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia; 6 Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea; 7 Department of Medical Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada; 8 F. Hoffmann-La Roche Ltd, Basel, Switzerland; 9 Roche Pharma AG, Grenzach-Wyhlen, Germany; 10 Christie Hospital, Withington, Manchester, United Kingdom 53

54 Study design Previously untreated mcrc, age 70 years N=280 Randomize 1:1 Capecitabine 1000 mg/m 2 b.i.d. days 1 14, q21d + Bevacizumab 7.5 mg/kg day 1, q21d Stratification factors: Capecitabine 1000 mg/m 2 b.i.d. days , q21d ECOG PS (0 1 vs 2) Geographic region Key inclusion criteria ECOG PS 0 2 Prior adjuvant chemotherapy allowed if completed >6 month before inclusion Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin Key exclusion criteria Prior chemotherapy for mcrc or prior adjuvant anti-vegf treatment Clinically significant cardiovascular disease Current or recent use of aspirin (>325 mg/day) or other NSAID Use of full-dose anticoagulants or thrombolytic agents 54

55 Progression-free survival PFS estimate Cape + BEV (n=140) Cape (n=140) HR=0.53 (95% CI: ) P< mo 9.1 mo Time (months) Number at risk Cape + BEV Cape ITT population. 113 PFS events in the Cape + BEV arm; 127 PFS events in the Cape arm. CI = confidence interval; PFS = progression-free survival 55

56 Subgroup analysis of PFS Cape + BEV better Cape alone better Category Subgroup N HR (95% CI) All All ( ) Sex Female ( ) Male ( ) Age <75 years ( ) 75 years ( ) Baseline ECOG performance status 0 > ( ) ( ) Prior adjuvant therapy No ( ) Yes ( ) Liver metastases only No ( ) Yes ( ) Surgical resection No ( ) Yes ( ) Location of primary disease Colon only ( ) Rectum and colon ( ) Rectum only ( ) HR ITT population. 56

57 Overall survival Cape + BEV (n=140) Cape (n=140) estimate OS HR=0.79 (95% CI: ) P= mo 20.7 mo Time (months) Number at risk Cape + BEV Cape ITT population. 75 OS events in each treatment arm. 57

58 Subsequent therapies Subsequent therapy (selected), % Cape + BEV (n=140) Cape (n=140) Any additional treatment for malignancy Fluorouracil Capecitabine Oxaliplatin-doublet Irinotecan-doublet Bevacizumab Cetuximab Panitumumab ITT population. 58

59 Study drug exposure dian treatment duration (months) Med Safety population. 59

60 Overview of adverse events AE, % Cape + BEV (n=134) Cape (n=136) Any AE SAE Grade 3 AE Grade 5 AE Any AE leading to dose modification AE leading to discontinuation Safety population. AE = adverse event; SAE = severe adverse event. 60

61 Conclusion AVEX is the first phase III trial to prospectively evaluate the use of a biologic in mcrc patients 70 years, a population that is in general undertreated The addition of BEV to cape significantly improved PFS and ORR PFS 9.1 vs 5.1 months (HR 0.53; p<0.001) ORR 19.3% vs 10.0% (p=0.042) A numerically longer OS was observed in the BEV-containing arm, but this did not reach statistical significance The safety profile was consistent with previously reported data of BEV in mcrc Results from AVEX suggest that the combination of BEV and cape is an effective and well-tolerated regimen for patients 70 years with mcrc 61

62 Remaining Questions What is the appropriate definition of elderly? 65? 70? 75? 80? (shifting ) What are the optimal screening and assessment tools for geriatric oncology patients? Quick and concise Specific to oncology? Specific to cancer site? What is the efficacy and tolerability of biologics and targeted agents in older cancer patients? 62

63 The Next Steps More data on tumor biology as a function of age To revisit the issue of adjuvant chemotherapy in the elderly with a clinical trial Differential toxicities Competing causes of death For now Individualize id elderly l care Start low and go slow Close and careful monitoring 63

64 The Next Steps BCCA GICOU First-line treatment choices and patterns in the elderly with mcrc Survey of elderly patients (and their physicians) about experiences during adjuvant treatment decision-making? Pilot testing of geriatric screening and/or assessment instruments Collaborations? 64

65 Questions? 65