1. Treatment of Elderly Patients with GI Cancer Treatment of Elderly Patients with GI Cancer D Papamichael MB BS FRCP 14 th World Congress on Gastrointestinal Cancer “Meet the Expert concurrent presentations” Barcelona, Spain 29 th June 2012

2. Outline Background Adjuvant therapy - Single agent 5FU-based therapy - Combination chemotherapy Management of metastatic disease Conclusions

3. Background Fastest growing section of population in Western countries is that of over 65s Approximately half the incidence of colorectal cancer occurs in the over 70s Evidence that elderly patients with colorectal cancer are: - under-staged - under-treated - under-represented in clinical trials

4. Percentage of total population aged 60 years or older 2002 The boundaries shown on this maps do not imply official endorsement by the United Nations http://www.un.org/esa/population/publications/ageing/Graph.pdf

5. Percentage of total population aged 60 years or older 2050 The boundaries shown on this maps do not imply official endorsement by the United Nations http://www.un.org/esa/population/publications/ageing/Graph.pdf

6. Background Fastest growing section of population in Western countries is that of over 65s Approximately half the incidence of colorectal cancer occurs in the over 70s Evidence that elderly patients with colorectal cancer are: - under-staged - under-treated - under-represented in clinical trials

7. Probability (%) of Developing Colorectal Cancer in the Next 10 Years by Age NCIC, Canadian Cancer Statistics 2002

8. http://data.un.org/Data.aspx?d=GenderStat&f=inID%3A36 Life Expectancy Women have a life expectancy of more than 20 years at 60, 15 years at 70 and 10 years at 80 Men of 20 years at 60, 12 years at 70 and 8 years at 80 F M Most recurrences of Stage III and high-risk Stage II colon cancer occur in the 3 years after surgery…Adjuvant chemotherapy should be considered

9. Background Fastest growing section of population in Western countries is that of over 65s Approximately half the incidence of colorectal cancer occurs in the over 70s Evidence that elderly patients with colorectal cancer are: - under-staged - under-treated - under-represented in clinical trials

10. FOCUS: Lancet 370:143-52, 2007UK Cancer Registry data

11. How is cancer treatment studied? Primarily middle-aged patients; minimal inclusion of older patients in clinical trials (approx. 20% of patients included in large adjuvant colorectal trials over 70 – median age at presentation is 71!) Minimal co-morbidities; patients with other medical problems excluded Caucasian Cancer centre based

12. Geriatric conditions that impact on life expectancy Co-morbidity: presence of 2 or more usually chronic conditions Disability: conditions that cause dependency in performing tasks Geriatric conditions: e.g. dementia, delirium, falls >3 clinically significant co-morbidities: life expectancy around 5 years Functional limitation: doubles 5 year mortality risk Geriatric syndromes: raise mortality risk by another 30% Geriatric assessment: can focus on physiologic or functional age rather than chronologic age

13. . Koroukian S M et al. JCO 2006;24:2304-2310

14. . Physicians agreement on importance of patient age and comorbidity Keating N L et al. JCO 2008;26:2532-2537

15. Pooled analysis – NSABP Trials 5FU (+LV or LEV) vs observation – stage II/III disease Individual patient data Total of 3351 patients / 7 studies Endpoints- OS / TTR - Toxicity - Deaths (with/without recurrence) Sargent et al NEJM 2001;345: 10091-7

16. Pooled analysis - NSABP Similar TTR and OS across all age groups - Consistent benefit - No significantly increased toxicity Death without cancer: 13% > 70 yrs 7% in 61-70 yrs 4% in 51-60 1% < 50 Sargent et al NEJM 2001;345: 10091-7

17. Elderly vs younger patients OS and DFS

18. Population based studies - 1 4768 stage III pts 65 or older 1992-1996 (SEER) Half received adjuvant therapy HR for death: 0.66 (95% CI 0.60-0.73) for 5FU based tx; i.e. 5FU based adjuvant therapy significantly associated with reduced mortality in older patients Sundararajan et al Ann Int Med 2002;136: 349-57

19. Population based studies - 2 85934 pts, stage III, NCBD 1990-2002 Lower use of adjuvant tx in elderly 80% in <70 70% in 70-79 40% in >80 Adjuvant chemotherapy increases survival in elderly as it does in younger patients Jessup et al JAMA 2005;294:2703-11

20. Population based studies – 3 Patients aged 75 or older with stage III colon carcinoma in the Netherlands -regional variation in adjuvant chemotherapy rates and improved survival Nationwide population-based study (9 regional cancer registries) 4462 patients who underwent resection for stage III colon cancer from 1997-2004 - 3104 (48%) aged 75-79 - 2102 (32%) aged 80-84 - 1263 (20%) aged 85 or older van Steenbergen et al Ann Oncol 2012 ;16(5):767-72(Epub)

21. Population based studies – 3 (cont.) Adjuvant therapy administered to 14% of patients - aged 75-7926% - aged 80-846% - aged 85 or older0.2% Males received adjuvant chemotherapy more often than females Rates of adjuvant chemotherapy use increased over time: from 10% in 1997 to 18% in 2004 van Steenbergen et al Ann Oncol 2012;16(5):767-772 (Epub)

22. X-ACT Dukes’ C colon Capecitabine 1250 mg/m 2 bid, d1–14, q21d n = 1004 Bolus 5-FU/LV 5-FU 425 mg/m 2 plus LV 20mg/m 2, d1–5, q28d n = 983 Recruitment 1998–2001 R 24 weeks Scheithauer et al Ann Oncol 2003;14: 1735-43

23. X-ACT - safety Effect of age on capecitabine toxicity -upper age limit 75 (but pts up to 82 yrs old included!) - safety profile analyzed for pts under and over 65 receiving capecitabine - result: no major differences -(consider renal impairement guidelines) - (capecitabine vs infusional 5FU?) Scheithauer et al Ann Oncol 2003;14: 1735-43

24. Stage II Colon Cancer

25. “Edrecolomab study” – 1738 patients Smoothing splines of (A) the log hazard for disease-specific disease-free survival by number of nodes examined truncated at 32 nodes, representing 95% of the data, and (B) the log hazard for disease-specific overall survival by age at trial entry with 95% confidence bands Niedzwiecki D et al. JCO 2011;29:3146-3152

26. Adjuvant chemotherapy for stage II older colon cancer patients with poor prognostic features 20,847 pts with stage II cancer (SEER database) Pts 66 and older, between 1992 and 2005 75% had at least one poor prognostic feature HR (1.02 vs 1.03, non-poor vs poor) for the benefit of chemotherapy O’Connor E et al J Clin Oncol 2011;29:3381-3388

27. Quick, simple & reliable 'Uncertain indication' for chemotherapy (3239 patients ’94 -’03) Observation (n=1617) 5-FU/LV ± Lev (n=1622) Randomize

28. 28

29. A pooled safety and efficacy analysis of FOLFOX4 in elderly compared to younger patients with colorectal cancer - Patients ≥70: n=614<70: n=3,128 Study A: MOSAIC-FOLFOX vs LV5FU2 adjuvant Rx FOLFOX: n=1,123 Study B: de Gramont et al-FOLFOX vs LV5FU2 1 st line Rx for mCRC FOLFOX: n=210 Study C: Goldberg et al-FOLFOX vs IFL vs IROX 1 st line Rx for mCRC FOLFOX: n=267 Study D:Rothenberg et al – FOLFOX vs IFL vs oxaliplatin 2 nd – line treatment for mCRC FOLFOX: n=281 Goldberg R M et al J Clin Oncol 2006; 24:4085-4091

30. MOSAIC adverse events Grade > 3 70 - any - non-heme - Deaths in 60 days No significant difference Goldberg, R. M. et al. J Clin Oncol 2006; 24:4085-4091

31. Forest plot of progression or disease-free survival by study for oxaliplatin plus fluorouracil/leucovorin administered bimonthly v control by age. de Gramont et al; MOSAIC; Rothenberg et al; Goldberg et al

32. Limitations Selected patients fit for trial inclusion MOSAIC eligibility – up to 75 Small numbers

33. Hazard ratios and 95% CIs for death in stage III patients administered oxaliplatin plus fluorouracil and leucovorin compared with stage III patients administered fluorouracil and leucovorin (FL) according to baseline prognostic factors (intent-to-treat population). André T et al. JCO 2009;27:3109-3116

34. Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients with stage II/III Colon cancer: Findings from the ACCENT database J McCleary, Meyerhardt, Green, Yothers, de Gramont, Van Cutsem, O’Connell, Twelves, Saltz, Sargent for the ACCENT collaborative group ASCO 2009

35. ACCENT: 6 trials Trial Accrual Period # pts % pts ≥ 70yrs Experimental treatment arm* % stage III+ MOSAIC1998-01224614FOLFOX460 X-ACT1998-01198320Capecitabine100 NSABP C-061997-99155723Uracif/legafur53 NSABP C-072000-02243416FLOX71 CALGB 89803 1999-01126324IFL98 PETACC-32000-02318613FOLFIRI71 *Compared to control arm of intravenous 5 fluorouracil ( IV 5 FU ) and leucovorin (LV)

36. Age Endpoint FR (95% Cl) Experimental v Control IV 5 FU/LV Deaths within 6 mo Exp v control % (p-value) DFS*OS*TTR* <70 n= 10,499 0.85 (0.80,0.91) 0.86 (0.79,0.92) 0.84 (0.79,0.91) 0.89 v 0.79 (p=0.58) ≥70 n=2,170 1.11 (0.97, 1.27) 1.14 (0.98, 1.32) 1.13 (0.97, 1.32) 2.71 v 2.11 (p=0.37) Interaction of age by treatment p-value 0.005 0.004 Efficacy – Overall population * Values < 1 favor experimental arm

37. Age Endpoint FR (95% Cl) Experimental v Control IV 5 FU/LV Deaths within 6 mo Exp vs control % (p- value) DFS*OS*TTR* <70 n= 3,977 0.77 (0.68,0.86) 0.81 (0.71,0.93) 0.76 (0.67,0.86) 0.81 v 0.81 (p=1.0) ≥70 n= 703 1.04 (0.080,1.35) 1.19 (0.90, 1.57) 0.92 (0.69, 1.32) 2.57 v 1.37 (p=0.25) Interaction of age by treatment p-value 0.0160.0370.21 Efficacy – Oxaliplatin-based therapy * Values < 1 favor experimental arm

38. Interpretation pitfalls No information for: - Toxicity data - Dose-intensity - Comorbidity This may confound interaction between age & newer adjuvant chemotherapy regimens (- Small population) (- Different FP regimens)

39. NSABP C-07 Percent Alive and Disease-Free Group Pts Events FULV 419 173 FLOX 455 137 HR 0.64 (0.51-0.80), P = 0.0001 Female < 70 Group Pts Events FULV 91 38 FLOX 81 34 HR 0.99 (0.62-1.57), P = 0.97 Female 70+ Group Pts Events FULV 587 222 FLOX 552 188 HR 0.87 (0.71-1.05), P = 0.15 Male < 70 Group Pts Events FULV 112 50 FLOX 112 53 HR 1.11 (0.76-1.64), P = 0.59 Male 70+ Multivariate Cox Models Show Treatment Interaction with Age and Gender DFS Yothers JCO 2011

40. NSABP C-07 Multivariate Cox Models Show Treatment Interaction with Age and Gender Group Pts Deaths FULV 419 119 FLOX 455 94 HR 0.67 (0.51-0.88), P=0.0035 Female < 70 Group Pts Deaths FULV 91 30 FLOX 81 28 HR 1.11 (0.66- 1.85),P=0.70 Female 70+ Group Pts Deaths FULV 587 145 FLOX 552 133 HR 0.95 (0.75-1.21), P=0.70 Male < 70 Group Pts Deaths FULV 112 38 FLOX 112 43 HR 1.22 (0.79-1.90),P=0.37 Male 70+ Percent Alive OS Yothers JCO 2011

41. D. Haller, J. Cassidy, J. Tabernero, J. Maroun F. de Braud, T. Price, E. Van Cutsem, M. Hill F. Gilberg, H-J. Schmoll Phase III Trial of Capecitabine + Oxaliplatin vs. Bolus 5-FU/LV in Stage III Colon Cancer (NO16968) Impact of Age on Disease-free Survival The third oxaliplatin trial

42. NO16968 Trial design Chemo/radiot herapy-naïve stage III colon ≤8 weeks since resection N=1886 RANDOMIZATIONRANDOMIZATION n=944 n=942 XELOX (6 months) capecitabine 1000mg/m 2 bid d1-14 oxaliplatin130mg/m 2 d1 q3w 8 cycles Bolus 5-FU/LV (6monts) Mayo Clinic (n=664) or Roswell Park (n=278) Primary endpoint: DFS secondary endpoints: RFS, OS, tolerability

43. DFS At 3, 4 and 5 Years: Benefit with XELOX Maintained and Increased Over Time 1.0 0.0 0.2 0.4 0.6 0.8 0123456 Years ITT population Δ at 4 years: 6.1% Δ at 5 years: 6.3% Δ at 3 years: 4.5% 70.9% 68.4% 3-year DFS 66.5% 62.3% 4-year DFS 5-year DFS 59.8% 66.1% XELOX 5-FU/LV

44. Comparison of NO16968 with ACCENT Analysis Hazard ratio (95% Cls)* DFSOS _____________________________________________________ ACCENT analysis 3+ <70 years, n=38770.77 (0.68,0.86)0.81 (0.71,0.93) ≥70 years, n=7031.04 (0.80, 1.35)1.18 (0.90, 1.57)(at 6 yrs) ____________________________________________________ NO16968 <70 years, n=14770.79 (0.66,0.94)0.86 (0.69,1.08) ≥70 years, n=4090.87 (0.63, 1.18)0.94 (0.66, 1.34) (at 3 yrs)(at 5 yrs) Values <1 favor Oxaliplatin-based therapy vs 5_FU/LV. + Data for Oxaliplatin-based regimens 3. McClearly et al, J Clin Oncol 2009;27 (suppl. 15s):Abstr 4010

45. Population and hazard-ratios N>70%DFS HROS HRReference ACCENT Oral FP 75521.31.131.17ASCO 2009 X-ACT a 39720.00.93 b Twelves NEJM 2005, ASCO GI 2008 C-0635822.3NA>1.13NA>1.17 Lembersky JCO 2006 ACCENT Oxaliplatin 70315.01.041.19ASCO 2009 MOSAIC315 c 14.00.911.10unpublished C-0738816.9NA>1.04NA>1.19 Kuebler JCO 2007 NO16968 a 40921.70.870.94ASCO GI 2010 a stage III b estimated from forest plot c stage III 190 patients

46. MOSAIC data in patients > 70 years OS Management of relapse and causes of death FOLFOXLV5FU2P N155160 Living with relapse713 Relapse5153 Chemotherapy23340.070 Irinotecan/oxali/(both)16:10/630:14/17/(1)0.011 Surgery Metastases9220.010 Death colon cancer2934 Death other22110.043 Second cancer910.020 Cardiovascular74

47. #3522: Impact of age and medical comorbidity (MC) for oxaliplatin on adjuvant treatment outcomes for stage III colon cancer (CC): a pooled analysis of individual patient data from four randomized controlled trials Haller DG, O’Connell M, Cartwright TH, Twelves C, McKenna EF, Sun W, Saif MW, Lee S, Yothers G, Schmoll H-J

48. 8,734 Total Stage III aCC Patients for Analysis X-ACT (n = 1,982) X-ACT (n = 1,982) LV/5-FU (n = 982) LV/5-FU (n = 982) Capecitabine (n = 1,000) Capecitabine (n = 1,000) XELOXA (n = 1,881) XELOXA (n = 1,881) LV/5-FU (n = 939) LV/5-FU (n = 939) XELOX (n = 942) XELOX (n = 942) NSABP C-08 (n = 2,004) NSABP C-08 (n = 2,004) mFOLFOX-6 (n = 1,001) mFOLFOX-6 (n = 1,001) mFOLFOX-6 + BV (n = 1,003) mFOLFOX-6 + BV (n = 1,003) AVANT (n = 2,867) AVANT (n = 2,867) FOLFOX-4 (n = 955) FOLFOX-4 (n = 955) FOLFOX-4 + BV (n = 960) FOLFOX-4 + BV (n = 960) Total LV/5-FU (n = 1,921) Total LV/5-FU (n = 1,921) Total XELOX/FOLFOX (n = 2,898) Total XELOX/FOLFOX (n = 2,898) XELOX + BV (n = 952) XELOX + BV (n = 952) Summary description of stage III cohorts 5-FU, 5-fluorouracil; aCC, adjuvant colon cancer; BV, bevacizumab; FOLFOX, leucovorin, 5-fluorouracil plus oxaliplatin; ITT, intention-to-treat; LV, leucovorin; XELOX, capecitabine plus oxaliplatin

49. Multivariate efficacy analyses Disease-free survivalOverall survival Effect/covariateHazard ratio95% CIPHazard ratio95% CIP Model including CCI Randomized treatment: XELOX/FOLFOX versus LV/5-FU0.660.59 to 0.73<.00010.620.55 to 0.71<.0001 Gender (female versus male)0.840.76 to 0.94.00200.850.75 to 0.96.0102 Age (<70 years versus ≥70 years)0.900.79 to 1.02.09830.770.66 to 0.89.0004 T-stage (T1–2 versus T3–4)0.570.46 to 0.71<.00010.560.43 to 0.73<.0001 N-stage (N1 versus N2)0.570.51 to 0.63<.00010.510.45 to 0.57<.0001 CCI (≤1 versus >1)0.790.69 to 0.90.00040.760.65 to 0.89.0005 Model including NCI Randomized treatment: XELOX/FOLFOX versus LV/5- FU0.660.59 to 0.73<.00010.620.55 to 0.71<.0001 Gender (female versus male)0.850.76 to 0.94.00210.850.75 to 0.96.0108 Age (<70 years versus ≥70 years)0.900.79 to 1.02.10240.770.66 to 0.89.0004 T-stage (T1–2 versus T3–4)0.570.46 to 0.71<.00010.560.43 to 0.73<.0001 N-stage (N1 versus N2)0.570.51 to 0.63<.00010.500.44 to 0.57<.0001 NCI (≤1 versus >1)0.800.70 to 0.91.00060.770.66 to 0.90.0007 CCI, Charlson Combined Index; CI, confidence interval; FOLFOX, leucovorin, fluorouracil plus oxaliplatin; LV/5-FU, leucovorin/5-fluorouracil; NCI, National Cancer Institute Combined Index; XELOX, capecitabine plus oxaliplatin

50. Oxaliplatin interaction analyses Disease-free survivalOverall survival Effect/covariateHazard ratio95% CIPHazard ratio95% CIP Model including CCI Randomized treatment: XELOX/FOLFOX versus LV/5-FU0.590.42 to 0.81.00140.650.45 to 0.95.0263 Gender (female versus male)0.860.77 to 0.97.01430.870.76 to 1.00.0517 Age (<70 years versus ≥70 years)0.860.71 to 1.04.11040.730.60 to 0.90.0031 T-stage (T1–2 versus T3–4)0.630.50 to 0.79<.00010.600.45 to 0.80.0005 N-stage (N1 versus N2)0.540.48 to 0.61<.00010.480.42 to 0.55<.0001 ECOG at baseline (0 versus 1)0.890.77 to 1.02.09420.850.72 to 1.00.0508 CCI (≤1 versus >1)0.720.60 to 0.88.00110.790.63 to 1.00.0478 Ox*age interaction (Ox/<70 versus rest)0.930.70 to 1.23.60800.920.67 to 1.28.6299 Ox*CCI interaction (Ox/≤1 versus rest)1.260.94 to 1.69.11971.090.77 to 1.54.6441 Model including NCI Randomized treatment: XELOX/FOLFOX versus LV/5-FU0.580.42 to 0.80.00090.620.43 to 0.90.0110 Gender (female versus male)0.860.77 to 0.97.01480.870.76 to 1.00.0526 Age (<70 years versus ≥70 years)0.860.71 to 1.04.11280.730.60 to 0.90.0033 T-stage (T1–2 versus T3–4)0.630.50 to 0.79<.00010.600.45 to 0.80.0005 N-stage (N1 versus N2)0.540.48 to 0.61<.00010.480.42 to 0.55<.0001 ECOG at baseline (0 versus 1)0.890.77 to 1.02.09510.850.72 to 1.00.0516 NCI (≤1 versus >1)0.730.60 to 0.88.00110.770.62 to 0.97.0234 Ox*age interaction (Ox/<70 versus rest)0.920.70 to 1.23.58930.920.66 to 1.27.5956 Ox*CCI interaction (Ox/≤1 versus rest)1.290.97 to 1.72.08161.170.83 to 1.65.3618 CCI, Charlson Combined Index; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FOLFOX, leucovorin, fluorouracil plus oxaliplatin; LV/5-FU, leucovorin/5-fluorouracil; NCI, National Cancer Institute Combined Index; Ox, oxaliplatin; XELOX, capecitabine plus oxaliplatin

51. Capecitabine alone, in stage III patients, may be a reasonable option XELOX or FOLFOX can still be considered for the DFS advantage… waiting for a new ACCENT analysis, and biomarkers to better identify the population that could benefit of oxaliplatin. (Can OS might be improved with a more intensive management at relapse ?.) (IDEA (International Duration Evaluation of Adjuvant Chemotherapy) A Prospective Pooled Analysis might give us some clues ) Which adjuvant treatment in ederly pts?

52. Conclusions – adjuvant therapy Toxicity probably not a major issue for “fit” elderly. Co- morbidities, functional status, PS, physiologic changes with age more relevant Gain may be inversely proportional to age due to increased deaths from other causes Oxaliplatin-based combination chemotherapy may be associated with decreased efficacy in the over 70s Multiple regimens to consider: 5FU/LV, capecitabine, FOLFOX or XELOX can all be considered as options, but (try to) discuss in light of recent data

53. Age dependent efficacy of 5-FU age 70 y70-7475-79>=80 n 3,19662948412520 OS11.310.810.99.413.4 (5.1-5.5)(5.2-5.8) p = 0.31 PFS5.35.55.55.56.4 (5.1-5.5)(5.2-5.8) p = 0.1 CR/PR21.1%23.9%24%26%(11%) p = 0.14 Folprecht et al. Ann Oncol 2004;15:1330-8

54. Efficacy and 5-FU administration 5-FUBolusinfus.Bolusinfus. n 20721124456173 OS10.712.311.311.9 p < 0.0001 p = 0.014 PFS4.85.95.25.8 p < 0.0001 p = 0.0002 CR/PR18.5%26.2%21.3%31.2% p < 0.0001 p = 0.014 age 70 y. Folprecht et al. Ann Oncol 2004;15:1330-8

55. Studies Included 1 Andre et al, NEJM 2004; 2 Goldberg et al, JCO 2004; 3 de Gramont et al, JCO 2000; 4 Rothenberg et al, JCO 2003

56. Efficacy, toxicity, dose intensity No difference in: - DFS, OS in 1 st line - OS 2 nd line - Adverse events - Dose intensity for 70

57. Folprecht G et al. J Clin Oncol 2008;26:1443-1451 EFFICACY< 70 years≥ 70 years≥ 75 years I-FUFU/FAI-FUFU/FAI-FUFU/FA Overall Survival, months 17.1 14.7 17.614.214.514.2 PFS, months 8.26.39.27.09.27.7 Overall Response, % 46.629.050.530.348.326.4 I-FU: irinotecan/fluorouracil/folinic acid FU/FA: fluorouracil/folinic acid Combined analysis on source data of 4 first-line, phase III trials - n=2691 patients (age ≥ 70 years, n=599; age < 70 years, n=2092 ) Irinotecan for mCRC in the elderly

58. Folprecht G et al. J Clin Oncol 2008;26:1443-1451

59. Incorporation of targeted therapies in the elderly with MCRC Three monoclonal antibodies have recently been registered for advanced colorectal cancer patients: cetuximab, panitumumab and bevacizumab Is there enough information about activity and toxicity of these drugs in the elderly population to recommend its use routinely?

60. Bevacizumab in combination with 5 FU/LV improves survival in patients with metastatic CRC: a combined analysis Probability of survival 1.0 0.8 0.6 0.4 0.2 0 010203040 Months since treatment initiation Median survival (months): 14.6 vs 17.9 HR=0.74, p=0.0081 5-FU/LV/Avastin 5mg (n=249) 5-FU/LV or IFL (n=241) 14.617.9 Kabbinavar et al. J Clin Oncol 2005;23:3706-3712 Median age 67y Range 23 – 90y

62. Safety and Effectiveness Outcomes, by age Subgroup in BRiTE All (N=1953) <65y (n=1057) 65-74 y (n=533) ≥75y (n=363) ≥80y (n=161) Safety,% GI perforation2.02.61.51.10.6 Post-op bleeding or WHCs5.15.54.5 3.8 ATE1.91.61.33.93.7 Grade ¾ bleeding2.62.23.42.51.2 New/worsening HTN20.720.520.621.221.1 Survival Median PFS, months9.910.29.79.89.2 1-yr survival rate, %74.477.172.569.465.8 Median OS, months23.527.321.319.516.2

63. “Your pulse may be too weak to be eligible for my study” Clinical Trials and the Elderly ?

64. Chemotherapy choices and doses in frail and elderly patients with advanced colorectal cancer MRC FOCUS2 Matt Seymour, Tim Maughan, Harpreet Wasan, Alison Brewster, Steve Shepherd, Sinead O’Mahoney, Beth May, Lindsay Thompson, Angela Meade and Ruth Langley, on behalf of The UK NCRI Colorectal Clinical Studies Group and FOCUS2 Investigators

65. FUOxFU CapOxCap Trial Design: 2x2 Factorial X

66. Progression free survival events total med PFS FU1111153.5 OxFU1101155.8 Cap1061155.2 OxCap1061145.8 FU OxFU Cap OxCap Factorial PFSHR (95% CI)p-value no oxaliplatin vs oxaliplatin [FU + Cap] vs [OxFU + OxCap] 0.84 (0.69, 1.01)0.07 FU vs capecitabine [FU = OxFU] vs [Cap + OxCap] 0.99 (0.82, 1.20)0.93

67. Quality of Life improvement Percentage of patients with improvement in EORTC QLQ-C30 global scale between baseline and week 12: Factorial QoL improvement% patientsp-value no oxaliplatin vs oxaliplatin [FU + Cap] vs [OxFU + OxCap] 62% vs 49%0.04 FU vs capecitabine [FU = OxFU] vs [Cap + OxCap] 56% vs 56%0.94

68. Response seen by 12 weeks n=450 (98%) patients with assessable disease at baseline Regimen FUOxFUCapOxCap randomised115 114 eligible, with measurable disease112111114113 %CR %PR %SD %PD, clinical deterioration or death % missing data 0 11.6 33.9 52.7 1.8 0.9 36.9 30.6 27.9 3.6 1.8 10.5 35.1 51.8 0.9 1.8 30.1 31.9 34.5 1.8 %CR+PR * 11.6 (reference) 37.8 p<0.0001 12.3 p=0.88 31.9 p<0.0001 * at 12 weeks. Responses seen only after 12 weeks not included Factorial Response% patientsp-value no oxaliplatin vs oxaliplatin [FU + Cap] vs [OxFU + OxCap] 13% vs 35%<0.0001 FU vs capecitabine [FU = OxFU] vs [Cap + OxCap] 24% vs 23%0.83

69. Toxicity by regimen RegimenFUOxFUCapOxCap n109 112109 Any Gr ≥3 toxicity24%29%37%41% 60d all-cause mortality11%3%6%7% Haemoglobin2.8% 0.9%1.8% Neutropenia2.8%4.6%1.8% Nausea0.9%1.8%5.4%4.6% Vomiting0.9%1.8%2.7%2.8% Anorexia2.8%1.8%5.4%3.7% Stomatitis0.9%1.8%0.9%1.8% Diarrhoea3.7%6.4%8.9%17.4% Pain8.3%4.6%9.8%5.5% Lethargy7.3%8.3%13.4%14.7% Peripheral Neuropathy0%0.9%0%3.7% Hand foot syndrome0% 9.8%0.9% Factorial Toxicityp-value no oxaliplatin vs oxaliplatin [FU + Cap] vs [OxFU + OxCap] worse with oxaliplatin: diarrhoea (6% vs 12%) sens. neuro (0% vs 2%) worse with no oxaliplatin: hand/foot derm (5% v 0.5%) 0.042 0.024 0.004 FU vs capecitabine [FU = OxFU] vs [Cap + OxCap] worse with capecitabine: any grade >3 tox (27% v 39%) nausea (1% v 5%) diarrhoea (5% v 13%) lethargy (8% v 14%) hand/foot derm. (0% v 5%) 0.006 0.032 0.003 0.037 <0.001

70. Overall Survival events total med OS FU 87115 9.7 OxFU 8411510.7 Cap 8311511.3 OxCap 8811412.4 Factorial Overall SurvivalHR (95% CI)p-value no oxaliplatin vs oxaliplatin [FU + Cap] vs [OxFU + OxCap] 0.99 (0.81, 1.18)p=0.91 FU vs capecitabine [FU = OxFU] vs [Cap + OxCap] 0.96 (0.79, 1.17)p=0.71

73. Balducci L and Extermann M. The Oncologist 2000;5:224-237 Comprehensive Geriatric Assessment Group 1: fit patients functionally independent no comorbidities Group 2: ‘in-between’ dependence in one activity 1-2 comorbidities Group 3: frail patients dependence for daily activities ≥ 3 comorbidities Life-prolonging TreatmentAdapted Treatment OnlyPalliation Cancer < Life Expectancy < Cancer

74. Conclusions – metastatic disease It is important to establish an overall treatment plan for the management of elderly metastatic CRC patients Age shouldn’t be the single decision parameter Assessment tools – collaboration in an MDT setting There is, as in younger patients, a need to identify the right patient for the right treatment (pharmacogenetics, pharmacogenomics, biomarkers etc.)

75. THANK YOU

76. Elderly colon cancer case Elderly colon cancer case

77. 78 yr old man, retired diplomat PR bleeding colonoscopy → lesion at 50cm → sigmoid colectomy (7/2009): –adenocarcinoma –T3N0(0/9)Mx –GII, vascular/lymphatic invasion

78. Past Medical History Pacemaker in situ for cardiac arrythmia Hypertension Renal stones Appendectomy as young adult Amlodipine 5 mg, od Metoprolol 200 mg, od Aspirin 75 mg, od Medications

79. Family history brother with colon ca at age 69, alive and well Social history Married with two sons, aged 41 and 45 years Smoking 1-2 cigars/day Occasional alcohol use Regular holidays around the year

80. 1. Would you administer adjuvant chemotherapy? 2. FU/LV or Oxaliplatin-based?

81. After discussion, he did not receive adjuvant treatment and was put on regular follow-up

82. Treatment options: 1. chemotherapy +/- surgery 2. up-front metastasectomy +/- chemo 3. chemotherapy 4. BSC 9/2011: elevated CEA (11.6 ng/ml) CT scan: single 4cm lesion on left liver lobe

84. Left liver lobectomy – November 2011 On 7 th post-op day: upper GI bleeding –Blood products support –Endoscopy: duodenal ulcer –PPIs Recovered uneventfully

85. Histology report Adenocarcinoma Consistent with colon primary Clear resection margins Further management 1.“adjuvant” chemotherapy? 2. Simple follow-up?

86. He decided to receive no further treatment 4 months later, CEA:1.2 ng/ml Last seen in clinic 6/2012: In radiological and marker CR