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Treatment of Elderly Patients with GI Cancer D Papamichael MB BS FRCP 14th World Congress on Gastrointestinal Cancer “Meet the Expert concurrent presentations” Barcelona, Spain 29th June 2012 Outline • Background • Adjuvant therapy - Single agent 5FU-based therapy - Combination chemotherapy • Management of metastatic disease • Conclusions 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 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 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 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 Probability (%) of Developing Colorectal Cancer in the Next 10 Years by Age NCIC, Canadian Cancer Statistics 2002 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 China 30 France China 30 France India 25 Japan India 25 Japan United Kingdom United Kingdom United States of America 20 15 15 10 10 5 5 0 United States of America 20 F 0 60 years 80 years M 60 years 80 years Most recurrences of Stage III and high-risk Stage II colon cancer occur in the 3 years after surgery…Adjuvant chemotherapy should http://data.un.org/Data.aspx?d=GenderStat&f=inID%3A36 be considered 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 relative frequency < 50 50-60 60-70 FOCUS patients FOCUS: Lancet 370:143-52, 2007 70-80 > 80 population UK Cancer Registry data 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 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 . Koroukian S M et al. JCO 2006;24:2304-2310 . Physicians agreement on importance of patient age and comorbidity Keating N L et al. JCO 2008;26:2532-2537 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 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 Elderly vs younger patients OS and DFS Population based studies - 1 • 4768 stage III pts 65 or older 1992-1996 • 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 (SEER) 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 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) Population based studies – 3 (cont.) • Adjuvant therapy administered to 14% of patients - aged 75-79 26% - aged 80-84 6% - aged 85 or older 0.2% • 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) X-ACT Dukes’ C colon Capecitabine 1250 mg/m2 bid, d1–14, q21d n = 1004 R 24 weeks Bolus 5-FU/LV 5-FU 425 mg/m2 plus LV 20mg/m2, d1–5, q28d n = 983 Scheithauer et al Ann Oncol 2003;14: 1735-43 Recruitment 1998–2001 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 Stage II Colon Cancer “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 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 Quick, simple & reliable 'Uncertain indication' for chemotherapy (3239 patients ’94 -’03) Randomize Observation (n=1617) 5-FU/LV ± Lev (n=1622) 28 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 1st line Rx for mCRC FOLFOX: n=210 • Study C: Goldberg et al-FOLFOX vs IFL vs IROX 1st line Rx for mCRC FOLFOX: n=267 • Study D:Rothenberg et al – FOLFOX vs IFL vs oxaliplatin 2nd – line treatment for mCRC FOLFOX: n=281 Goldberg R M et al J Clin Oncol 2006; 24:4085-4091 MOSAIC adverse events Grade > 3 • < 70 vs > 70 - any - non-heme - Deaths in 60 days No significant difference Goldberg, R. M. et al. J Clin Oncol 2006; 24:4085-4091 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 Goldberg, R. M. et al. J Clin Oncol 2006; 24: 4085-4091 Limitations • Selected patients fit for trial inclusion • MOSAIC eligibility – up to 75 • Small numbers 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 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 ACCENT: 6 trials # pts % pts ≥ 70yrs Experimental treatment arm* % stage III+ 1998-01 2246 14 FOLFOX4 60 X-ACT 1998-01 1983 20 Capecitabine 100 NSABP C-06 1997-99 1557 23 Uracif/legafur 53 NSABP C-07 2000-02 2434 16 FLOX 71 CALGB 89803 1999-01 1263 24 IFL 98 PETACC-3 2000-02 3186 13 FOLFIRI 71 Trial Accrual Period MOSAIC *Compared to control arm of intravenous 5 fluorouracil ( IV 5 FU ) and leucovorin (LV) Efficacy – Overall population Age <70 n= 10,499 ≥70 n=2,170 Interaction of age by treatment p-value Endpoint FR (95% Cl) Experimental v Control IV 5 FU/LV Deaths within 6 mo Exp v control % (p-value) DFS* OS* TTR* 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) 1.11 1.14 1.13 (0.97, 1.27) (0.98, 1.32) (0.97, 1.32) 2.71 v 2.11 (p=0.37) 0.005 0.005 * Values < 1 favor experimental arm 0.004 Efficacy – Oxaliplatin-based therapy Age <70 n= 3,977 ≥70 n= 703 Interaction of age by treatment p-value DFS* OS* TTR* Deaths within 6 mo Exp vs control % (pvalue) 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) 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) 0.016 0.037 0.21 Endpoint FR (95% Cl) Experimental v Control IV 5 FU/LV * Values < 1 favor experimental arm 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) Male < 70 60 80 Female < 70 Group Pts Events FULV 587 222 FLOX 552 188 HR 0.87 (0.71-1.05), P = 0.15 20 40 Group Pts Events FULV 419 173 FLOX 455 137 HR 0.64 (0.51-0.80), 100 0 P = 0.0001 Male 70+ 60 80 Female 70+ 20 40 Group Pts Events FULV 91 38 FLOX 81 34 HR 0.99 (0.62-1.57), P = 0.97 Group Pts Events FULV 112 50 FLOX 112 53 HR 1.11 (0.76-1.64), P = 0.59 0 Percent Alive and Disease-Free DFS 100 NSABP C-07 0 2 4 6 8 0 2 4 6 8 Multivariate Cox Models Show Treatment Interaction with Age and Gender Yothers JCO 2011 NSABP C-07 Male < 70 Female < 70 100 0 20 40 Group Pts Deaths FULV 419 119 FLOX 455 94 HR 0.67 (0.51-0.88), P=0.0035 Group Pts Deaths FULV 587 145 FLOX 552 133 HR 0.95 (0.75-1.21), P=0.70 Male 70+ 60 80 Female 70+ Group Pts Deaths FULV 91 30 FLOX 81 28 HR 1.11 (0.661.85),P=0.70 Group Pts Deaths FULV 112 38 FLOX 112 43 HR 1.22 (0.79-1.90),P=0.37 0 20 40 Percent Alive 60 80 100 OS 0 2 4 6 8 0 2 4 Multivariate Cox Models Show Treatment Interaction with Age and Gender 6 8 Yothers JCO 2011 Phase III Trial of Capecitabine + Oxaliplatin vs. Bolus 5-FU/LV in Stage III Colon Cancer (NO16968) Impact of Age on Disease-free Survival D. Haller, J. Cassidy, J. Tabernero, J. Maroun F. de Braud, T. Price, E. Van Cutsem, M. Hill F. Gilberg, H-J. Schmoll The third oxaliplatin trial NO16968 Trial design Chemo/radiot herapy-naïve stage III colon ≤8 weeks since resection N=1886 R A N D O M I Z A T I O N n=944 n=942 • Primary endpoint: DFS • secondary endpoints: RFS, OS, tolerability XELOX (6 months) capecitabine 1000mg/m2 bid d1-14 oxaliplatin130mg/m2 d1 q3w 8 cycles Bolus 5-FU/LV (6monts) Mayo Clinic (n=664) or Roswell Park (n=278) Comparison of NO16968 with ACCENT Analysis Hazard ratio (95% Cls)* DFS OS _____________________________________________________ ACCENT analysis 3+ <70 years, n=3877 0.77 (0.68,0.86) 0.81 (0.71,0.93) ≥70 years, n=703 1.04 (0.80, 1.35) 1.18 (0.90, 1.57) (at 6 yrs) (at 6 yrs) ____________________________________________________ NO16968 <70 years, n=1477 0.79 (0.66,0.94) 0.86 (0.69,1.08) ≥70 years, n=409 0.87 (0.63, 1.18) (at 3 yrs) 0.94 (0.66, 1.34) (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 Population and hazard-ratios N>70 % DFS HR OS HR Reference 755 21.3 1.13 1.17 ASCO 2009 0.93 b Twelves NEJM 2005, ASCO GI 2008 ACCENT Oral FP X-ACT a 20.0 C-06 358 22.3 ACCENT Oxaliplatin 703 15.0 1.04 1.19 ASCO 2009 315 c 14.0 0.91 1.10 unpublished C-07 388 16.9 NO16968 a 409 21.7 MOSAIC a 0.93 b 397 stage III b estimated from forest plot NA>1.13 NA>1.17 NA>1.04 NA>1.19 0.87 c stage 0.94 III 190 patients Lembersky JCO 2006 Kuebler JCO 2007 ASCO GI 2010 MOSAIC data in patients > 70 years OS Management of relapse and causes of death FOLFOX LV5FU2 155 160 Living with relapse 7 13 Relapse 51 53 Chemotherapy 23 34 0.070 16:10/6 30:14/17/(1) 0.011 Surgery Metastases 9 22 0.010 Death colon cancer 29 34 Death other 22 11 0.043 Second cancer 9 1 0.020 Cardiovascular 7 4 N Irinotecan/oxali/(both) P #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 Summary description of stage III cohorts 8,734 Total Stage III aCC Patients for Analysis X-ACT (n = 1,982) LV/5-FU (n = 982) Capecitabine (n = 1,000) XELOXA (n = 1,881) LV/5-FU (n = 939) NSABP C-08 (n = 2,004) XELOX (n = 942) mFOLFOX-6 (n = 1,001) mFOLFOX-6 + BV (n = 1,003) FOLFOX-4 (n = 955) Total LV/5-FU (n = 1,921) Total XELOX/FOLFOX (n = 2,898) 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 AVANT (n = 2,867) FOLFOX-4 + BV (n = 960) XELOX + BV (n = 952) Multivariate efficacy analyses Disease-free survival Effect/covariate Overall survival Hazard ratio 95% CI P Hazard ratio 95% CI P Randomized treatment: XELOX/FOLFOX versus LV/5-FU 0.66 0.59 to 0.73 <.0001 0.62 0.55 to 0.71 <.0001 Gender (female versus male) 0.84 0.76 to 0.94 .0020 0.85 0.75 to 0.96 .0102 Age (<70 years versus ≥70 years) 0.90 0.79 to 1.02 .0983 0.77 0.66 to 0.89 .0004 T-stage (T1–2 versus T3–4) 0.57 0.46 to 0.71 <.0001 0.56 0.43 to 0.73 <.0001 N-stage (N1 versus N2) 0.57 0.51 to 0.63 <.0001 0.51 0.45 to 0.57 <.0001 CCI (≤1 versus >1) 0.79 0.69 to 0.90 .0004 0.76 0.65 to 0.89 .0005 Randomized treatment: XELOX/FOLFOX versus LV/5FU 0.66 0.59 to 0.73 <.0001 0.62 0.55 to 0.71 <.0001 Gender (female versus male) 0.85 0.76 to 0.94 .0021 0.85 0.75 to 0.96 .0108 Age (<70 years versus ≥70 years) 0.90 0.79 to 1.02 .1024 0.77 0.66 to 0.89 .0004 T-stage (T1–2 versus T3–4) 0.57 0.46 to 0.71 <.0001 0.56 0.43 to 0.73 <.0001 N-stage (N1 versus N2) 0.57 0.51 to 0.63 <.0001 0.50 0.44 to 0.57 <.0001 NCI (≤1 versus >1) 0.80 0.70 to 0.91 .0006 0.77 0.66 to 0.90 .0007 Model including CCI Model including NCI 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 Oxaliplatin interaction analyses Effect/covariate Model including CCI Randomized treatment: XELOX/FOLFOX versus LV/5-FU Gender (female versus male) Age (<70 years versus ≥70 years) T-stage (T1–2 versus T3–4) N-stage (N1 versus N2) ECOG at baseline (0 versus 1) CCI (≤1 versus >1) Ox*age interaction (Ox/<70 versus rest) Ox*CCI interaction (Ox/≤1 versus rest) Model including NCI Randomized treatment: XELOX/FOLFOX versus LV/5-FU Gender (female versus male) Age (<70 years versus ≥70 years) T-stage (T1–2 versus T3–4) N-stage (N1 versus N2) ECOG at baseline (0 versus 1) NCI (≤1 versus >1) Ox*age interaction (Ox/<70 versus rest) Ox*CCI interaction (Ox/≤1 versus rest) Disease-free survival Hazard ratio 95% CI P Overall survival Hazard ratio 95% CI P 0.59 0.86 0.86 0.63 0.54 0.89 0.72 0.42 to 0.81 0.77 to 0.97 0.71 to 1.04 0.50 to 0.79 0.48 to 0.61 0.77 to 1.02 0.60 to 0.88 .0014 .0143 .1104 <.0001 <.0001 .0942 .0011 0.65 0.87 0.73 0.60 0.48 0.85 0.79 0.45 to 0.95 0.76 to 1.00 0.60 to 0.90 0.45 to 0.80 0.42 to 0.55 0.72 to 1.00 0.63 to 1.00 .0263 .0517 .0031 .0005 <.0001 .0508 .0478 0.93 1.26 0.70 to 1.23 0.94 to 1.69 .6080 .1197 0.92 1.09 0.67 to 1.28 0.77 to 1.54 .6299 .6441 0.58 0.86 0.86 0.63 0.54 0.89 0.73 0.42 to 0.80 0.77 to 0.97 0.71 to 1.04 0.50 to 0.79 0.48 to 0.61 0.77 to 1.02 0.60 to 0.88 .0009 .0148 .1128 <.0001 <.0001 .0951 .0011 0.62 0.87 0.73 0.60 0.48 0.85 0.77 0.43 to 0.90 0.76 to 1.00 0.60 to 0.90 0.45 to 0.80 0.42 to 0.55 0.72 to 1.00 0.62 to 0.97 .0110 .0526 .0033 .0005 <.0001 .0516 .0234 0.92 1.29 0.70 to 1.23 0.97 to 1.72 .5893 .0816 0.92 1.17 0.66 to 1.27 0.83 to 1.65 .5956 .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 Which adjuvant treatment in ederly pts? 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 ) Conclusions – adjuvant therapy • Toxicity probably not a major issue for “fit” elderly. Comorbidities, 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 Age dependent efficacy of 5-FU age < 70 y > 70 y 70-74 75-79 >=80 n 3,196 629 484 125 20 OS 11.3 10.8 10.9 9.4 13.4 (5.1-5.5) (5.2-5.8) 5.5 5.5 6.4 24% 26% (11%) p = 0.31 PFS 5.3 5.5 (5.1-5.5) (5.2-5.8) p = 0.1 CR/PR 21.1% 23.9% p = 0.14 Folprecht et al. Ann Oncol 2004;15:1330-8 Efficacy and 5-FU administration age < 70 y. > 70 y. 5-FU Bolus infus. Bolus infus. n 2072 1124 456 173 OS 10.7 12.3 11.3 11.9 p < 0.0001 PFS 4.8 p = 0.014 5.9 p < 0.0001 CR/PR 18.5% 26.2% p < 0.0001 Folprecht et al. Ann Oncol 2004;15:1330-8 5.2 5.8 p = 0.0002 21.3% p = 0.014 31.2% Studies Included Study Comparator Setting regimen N MOSAIC1 5-FU/LV Adjuvant 2246 N97412 IFL 1st Line 546 de Gramont3 5-FU/LV 1st Line 420 Rothenberg4 5-FU/LV 2nd Line 531 Total 1Andre et al, NEJM 2004; 2Goldberg et al, JCO 2004; 3de Gramont et al, JCO 2000; 4Rothenberg et al, JCO 2003 3743 Efficacy, toxicity, dose intensity No difference in: - DFS, OS in 1st line - OS 2nd line - Adverse events - Dose intensity for <70 vs >70 Irinotecan for mCRC in the elderly 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) < 70 years ≥ 70 years ≥ 75 years I-FU FU/FA I-FU FU/FA I-FU FU/FA • Overall Survival, months 17.1 14.7 17.6 14.2 14.5 14.2 • PFS, months 8.2 6.3 9.2 7.0 9.2 7.7 • Overall Response, % 46.6 29.0 50.5 30.3 48.3 26.4 EFFICACY I-FU FU/FA : irinotecan/fluorouracil/folinic acid : fluorouracil/folinic acid Folprecht G et al. J Clin Oncol 2008;26:1443-1451 Folprecht G et al. J Clin Oncol 2008;26:1443-1451 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? Bevacizumab in combination with 5 FU/LV improves survival in patients with metastatic CRC: a combined analysis Probability of survival 1.0 Median survival (months): 14.6 vs 17.9 HR=0.74, p=0.0081 0.8 0.6 5-FU/LV/Avastin 5mg (n=249) 5-FU/LV or IFL (n=241) 0.4 0.2 14.6 17.9 0 0 Median age 67y Range 23 – 90y 10 20 30 40 Months since treatment initiation Kabbinavar et al. J Clin Oncol 2005;23:3706-3712 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 perforation 2.0 2.6 1.5 1.1 0.6 Post-op bleeding or WHCs 5.1 5.5 4.5 4.5 3.8 ATE 1.9 1.6 1.3 3.9 3.7 Grade ¾ bleeding 2.6 2.2 3.4 2.5 1.2 New/worsening HTN 20.7 20.5 20.6 21.2 21.1 Median PFS, months 9.9 10.2 9.7 9.8 9.2 1-yr survival rate, % 74.4 77.1 72.5 69.4 65.8 Median OS, months 23.5 27.3 21.3 19.5 16.2 Survival Clinical Trials and the Elderly ? “Your pulse may be too weak to be eligible for my study” MRC FOCUS2 Chemotherapy choices and doses in frail and elderly patients with advanced colorectal cancer 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 Trial Design: 2x2 Factorial FU OxFU X Cap OxCap Progression free survival 1.00 Progression Free Survival eventsEvents total MdG->OxMdG FU 111 OxMdG OxFU 110 Cap 106 MdG->OxCap OxCap 106 OxCap 0.75 Factorial PFS 111 115 110 115 115 106 114 106 Total med PFS 115 3.5 115 5.8 5.2 115 5.8 114 HR (95% CI) p-value 0.84 (0.69, 1.01) 0.07 0.99 (0.82, 1.20) 0.93 0.50 no oxaliplatin vs oxaliplatin 0.25 [FU + Cap] vs [OxFU + OxCap] FU vs capecitabine 0.00 [FU = + OxCap] 0 OxFU] vs [Cap 3 6 At risk: FU OxFU Cap OxCap 115 115 115 114 76 90 76 90 36 48 37 46 9 Time (Months) 12 15 18 15 17 14 16 8 10 8 7 5 3 7 2 3 1 5 1 Quality of Life improvement • Percentage of patients with improvement in EORTC QLQ-C30 global scale between baseline and week 12: Factorial QoL improvement no oxaliplatin vs oxaliplatin [FU + Cap] vs [OxFU + OxCap] FU vs capecitabine [FU = OxFU] vs [Cap + OxCap] % patients p-value 62% vs 49% 0.04 56% vs 56% 0.94 Response seen by 12 weeks n=450 (98%) patients with assessable disease at baseline Factorial Response Regimen FU% patients OxFU Cap p-value OxCap randomised 115 115 no oxaliplatin vs oxaliplatin eligible, with measurable disease 112 111 13% vs 35% 0 0.9 11.6 36.9 33.9 30.6 52.7 24% vs27.9 23% 1.8 3.6 [FU + Cap] vs [OxFU + OxCap] %CR %PR %SD FU vs capecitabine %PD, clinical deterioration or death % missing [FU = data OxFU] vs [Cap + OxCap] %CR+PR* * at 12 weeks. Responses seen only after 12 weeks not included 115 114 114 113 <0.0001 1.8 1.8 10.5 30.1 35.1 31.9 51.8 34.5 0.83 0.9 1.8 11.6 37.8 12.3 31.9 (reference) p<0.0001 p=0.88 p<0.0001 Toxicity by regimen Regimen Factorial Toxicity n FU OxFU Cap OxCap 109 109 112 109 Any Gr ≥3 toxicity 24% 29% 37% worse with oxaliplatin: 60d all-cause mortality 11% 3% 6% diarrhoea (6% vs 12%) no oxaliplatin vs oxaliplatin 2.8% sens. neuro (0% vs 2%) 2.8% 0.9% Haemoglobin [FU + Cap] vs [OxFU + OxCap] Neutropenia p-value 41% 7% 1.8% 0.042 0.024 1.8% Nausea 2.8% 4.6% 1.8% worse with no oxaliplatin: hand/foot1.8% derm (5% v5.4% 0.5%) 0.9% Vomiting 0.9% 2.8% Anorexia 2.8% 5.4% 3.7% worse with1.8% capecitabine: any grade >3 tox (27% v 39%) 1.8% 0.006 0.9% 1.8% 0.9% nausea (1% v 5%) 0.032 3.7% 8.9% 17.4% 0.003 diarrhoea6.4% (5% v 13%) lethargy (8% v 14%) 0.037 8.3% 4.6% 9.8% 5.5% hand/foot derm. (0% v 5%) <0.001 7.3% 8.3% 13.4% 14.7% Stomatitis FU vs capecitabine Diarrhoea [FU = OxFU] vs [Cap + OxCap] Pain Lethargy 1.8% 2.7% 4.6% Peripheral Neuropathy 0% 0.9% 0% 3.7% Hand foot syndrome 0% 0% 9.8% 0.9% 0.004 Overall Survival 1.00 Overall Survival Factorial Overall Survival 0.75 0.50 no oxaliplatin vs oxaliplatin [FU + Cap] vs [OxFU + OxCap] events MdG->OxMdG FU 87 OxMdG OxFU 84 FU vs capecitabine Cap 83 MdG->OxCap OxCap 88 [FU = OxFU] OxCap vs [Cap + OxCap] 0.00 0.25 0 3 6 At risk: 115 94 81 115 115 102 94 114 100 Events total 87 115 84 115 115 83 114 88 HR (95% CI) p-value 0.99 (0.81, 1.18) p=0.91 Total med OS 115 9.7 115 10.7 11.3 115 (0.79, 1.17) 0.96 12.4 114 9 Time (Months) p=0.71 12 15 18 60 38 29 15 82 78 62 62 43 44 30 29 20 23 81 67 49 28 16 Comprehensive Geriatric Assessment Group 1: fit patients Group 2: ‘in-between’ Group 3: frail patients • functionally independent • dependence in one activity • dependence for daily activities • no comorbidities • 1-2 comorbidities • ≥ 3 comorbidities Cancer < Life Expectancy < Cancer Life-prolonging Treatment Adapted Treatment Only Balducci L and Extermann M. The Oncologist 2000;5:224-237 Palliation 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.) THANK YOU Elderly colon cancer case 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 Past Medical History Pacemaker in situ for cardiac arrythmia Hypertension Renal stones Appendectomy as young adult Medications Amlodipine 5 mg, od Metoprolol 200 mg, od Aspirin 75 mg, od 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 1. Would you administer adjuvant chemotherapy? 2. FU/LV or Oxaliplatin-based? After discussion, he did not receive adjuvant treatment and was put on regular follow-up 9/2011: elevated CEA (11.6 ng/ml) CT scan: single 4cm lesion on left liver lobe Treatment options: 1. chemotherapy +/- surgery 2. up-front metastasectomy +/- chemo 3. chemotherapy 4. BSC Left liver lobectomy – November 2011 On 7th post-op day: upper GI bleeding – Blood products support – Endoscopy: duodenal ulcer – PPIs Recovered uneventfully Histology report Adenocarcinoma Consistent with colon primary Clear resection margins Further management 1.“adjuvant” chemotherapy? 2. Simple follow-up? 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