1. Capecitabine and Oxaliplatin in elderly and/or frail patients with Metastatic Colorectal Cancer: MRC trial FOCUS2 M. T. Seymour 1, T. S. Maughan 2, H. S. Wasan 3, A. E. Brewster 4, S. F. Shepherd 5, M. S. O'Mahoney 6, B. R. May 7, L. C. Thompson 7, A. M. Meade 7, R. E. Langley 7, on behalf of the UK National Cancer Research Institute Colorectal Clinical Studies Group and the FOCUS2 Investigators. Institutions: 1 Cancer Research UK Clinical Centre, Leeds, Leeds, UK, 2 Velindre Hospital, Wales, UK, 3 Hammersmith Hospital, London, UK, 4 Velindre NHS Trust, Wales, UK, 5 Cheltenham General Hospital, Cheltenham, UK, 6 Cardiff University, Wales, UK, 7 MRC Clinical Trials Unit, London, UK

2. Background: Elderly/frail patients, though commonly treated, are under-represented in clinical trials. Evidence is needed to guide choices of drugs and doses in this population. Methods: FOCUS2 is a multicenter, 2x2 factorial randomized trial for patients with unpretreated metastatic colorectal cancer judged unfit for full-dose combination chemo­therapy. After comprehensive health assessment (CHA), randomization was to: (A) simplified LV5FU2 infusional fluorouracil/leucovorin (FU); (B) OxFU; (C) Cap; or (D) OxCap. In each case, starting doses were 80% standard, with an option to escalate to full-dose at 6 weeks (wk). The factorial questions were: (A+B v C+D) - does replacing FU with Cap improve quality of life (QL)? (primary endpoint: improved global QL at 12 wk [QLQ-C30]); and (A+C v B+D) - how much does Ox improve efficacy in this population? (primary endpoint: progression-free survival (PFS). Results: 460 patients were randomized, 22% 75 yrs. 22% were performance status (PS) 0; 49% PS1; 29% PS2. Primary comparisons (see table): global QL did not favor Cap over FU. Comparison of PFS favored the addition of oxaliplatin but did not reach significance (HR 0.87, 95% CI 0.71-1.06, p=0.16). Secondary comparisons: Compared with FU, Cap did not affect RR, PFS or 60-day mortality, but it increased the risk of gr ≥3 toxicity. Oxaliplatin significantly improved RECIST response (RR) by wk 12, did not increase gr ≥3 toxicity or 60-day mortality, but reduced the chance of improved QL at 12 wk. * primary endpoint Conclusion: In this frail elderly population, substituting Cap for FU avoided the need for indwelling venous access but did not improve overall QL or efficacy, and significantly increased toxicity. Addition of Ox gave significantly higher anticancer activity without increasing toxicity, but at the cost of some reduction in QL at 12 wk. Planned analyses include correlating baseline CHA with treatment outcome.

3. Background Elderly and frail advanced colorectal cancer patients… …are a high proportion of real-life practice Median age at death with colorectal cancer in UK is 75 yrs …are under-represented in clinical trials Median age in most metastatic CRC trials 60-63 years Subgroup analyses of elderly patients in those trials have been done, but represent a highly selected group …are commonly treated with unevaluated regimens In a postal survey of UK MRC trial centres in 2002: for every 10 patients treated on trials, a further 17 were being treated off-trial. Usually treated with reduced-dose and/or single-agent regimens.

4. Aims of this trial To evaluate chemotherapy regimens in frail/elderly Does replacing optimum infusional FU with oral capecitabine improve patients’ quality of life? Does addition of oxaliplatin give similar benefit as in young and fit patients? To evaluate tolerability of reduced chemotherapy doses Start regimens at 80% of standard chemotherapy doses: is tolerability comparable with 100% dose in standard patients? evaluate ability/willingness escalate to 100% after 6 weeks. To develop and evaluate an objective assessment tool Can a comprehensive objective health assessment be applied to frail/elderly patients in the multicenter oncology clinic setting? Does it contribute to our assessment of outcomes? Could it predict tolerability and outcomes, and so be used to guide future treatment choices?

5. Patients and Methods Prospective randomised clinical trial for patients with non-pretreated metastatic colorectal cancer considered unsuitable for standard full-dose combination chemotherapy because of advanced age and/or frailty Patient selection and consent comprehensive health assessment (see below) Randomisation All chemotherapy doses 80% of standard increase to 100% after 6weeks if patient happy and no major toxicity Primary Outcomes: PFS, QoL Secondary outcomes: toxicity; OS

6. A FU alone 1 st line (OxFU reserved for 2 nd line) B OxFU 1 st line C Cap alone 1 st line (OxCap reserved for 2 nd line) D OxCap 1 st line Trial Design: 2x2 Factorial Factorial Comparison 2 Does the addition of oxaliplatin improve PFS? Expected PFS arms A and C is 50% at 6 months. 460 patients will detect an increase from 50% to 65% (90% power; 2-sided 5% significance; log rank test). Factorial Comparison 1 Does capecitabine give better QL improvement than FU? 260 patients with data 0 and 12 wks gives 90% power to detect increase from 40% to 60% with improved overall QL (2-sided chi-sq; 5% significance). versus

7. The regimens 80% standard dose* FU OxFU Cap OxCap * as in FOCUS Trial, Seymour et al, ASCO 23:3518, 2005, currently in press: The Lancet 2007 (l-LV 175 mg; FU 320 mg/m 2 bolus; FU 2240mg/m 2 over 46 hr every 2 weeks) (Ox 68 mg/m 2 ; LV and FU as above except 1920mg/m 2 over 46 hr every 2 weeks) (Capecitabine 1000 mg/m 2 b.d. for 14-days, every 3 weeks) (Ox 104 mg/m 2 d1; Cap 800 mg/m 2 b.d. for 14 days, every 3 weeks) 80% standard dose* 80% standard dose

8. Comprehensive Geriatric Health Assessment 117-point assessment tool Physical/nutritional assessment Mental state (MMSE) Medical co-morbidity (Charlson) Activities of daily living (Nottingham) Anxiety and depression (HADS) QL/Symptom checklist (QLQ-C30) Medical resource usage (EQ5D)

9. Patient Characteristics FUOxFUCapOxCap n115 114 Male Female 73 (63%) 42 (37%) 69 (60%) 46 (40%) 68 (59%) 47 (41%) 68 (60%) 46 (40%) Age:Median (years) Interquartile (years) 75 71-78 75 71-78 73 69-78 75 70-79 Primary Rectum Primary Colon 25 (22%) 68 (59%) 30 (26%) 59 (51%) 31 (28%) 64 (56%) 34 (30%) 60 (53%) WHO Performance Status: 0 1 2 25 (22%) 58 (50%) 32 (28%) 23 (20%) 57 (50%) 35 (30%) 23 (20%) 40 (25%) 34 (30%) 27 (24%) 54 (47%) 33 (29%) Metastases: Liver Nodes Lung Peritoneum Other 83 (73%) 58 (51%) 46 (40%) 27 (24%) 16 (14%) 87 (78%) 43 (38%) 53 (47%) 22 (20%) 10 (9%) 84 (74%) 49 (43%) 43 (38%) 20 (18%) 10 (9%) 87 (77%) 37 (33%) 40 (35%) 14 (12%) 18 (16%)

10. Dose increase at 6 weeks If no significant toxicity present, then after 6 weeks a discretionary dose increase to 100% was considered… FUOxFUCapOxCap

11. Primary Endpoints

12. Progression-free survival: 0.00 0.25 0.50 0.75 1.00 Progression Free Survival 0369121518 Time (Months) FU 108 115 OxFU 110 115 Cap 106 115 OxCap 105 115 Events Total Addition of oxaliplatin [FU vs OxFU] + [Cap vs OxCap] HR=0.83; p=0.06 Substitution of FU with Cap [FU vs Cap] + [OxFU vs OxCap] HR=1.00; p=0.96 ABCDABCD

13. Quality of Life improvement (1) EORTC QLQ-C30 global scale: Percentage of patients with improvement in between baseline and week 12: Substitution of FU with Cap [FU vs Cap] + [OxFU vs OxCap] 55% vs 56%; p=0.89 Addition of oxaliplatin [FU vs OxFU] + [Cap vs OxCap] 62% vs 49%; p=0.04

14. Quality of Life improvement (2) Improved at 12 wks (n=197) FUOxFUCapOxCapFU vs Cap±Ox Overall54%51%37%40% 52% vs 38% p=0.05 46% vs 46% p=0.99 Mobility59%63%39%51% 61% vs 47% p=0.02 50% vs 58% p=0.25 Kitchen78%71%75%74% 75% vs 74% p=0.96 76% vs 73% p=0.59 Domestic67%69%59%63% 68% vs 61% p=0.28 63% vs 66% p=0.61 Leisure56%65%59%51% 60% vs 55% p=0.49 57% vs 59% p=0.83 Nottingham Extended Health ADL: Percentage of patients with improvement in score between baseline and week 12:

15. Secondary Endpoints

16. RECIST Responses Assessed at 12 weeks

17. Toxicity by regimen Regimen5FUOx5FUCapOxCap 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%

18. Toxicity – Factorial Analysis FactorialSubstitution of CapAddition of oxali Regimens FU/ OxFU Cap/ OxCap p FU/ Cap OxFU/ OxCap p Any Gr ≥327%39%0.00630%35%ns Haemoglobin3%1%ns2% ns Neutropenia4%2%ns2%3%ns Nausea1%5%0.0323% ns Vomiting1%3%ns2% ns Anorexia2%5%ns4%3%ns Stomatitis1% ns1%2%ns Diarrhoea5%13%0.0036%12%0.042 Pain6%8%ns9%5%ns Lethargy8%14%0.03710%11%ns Periph. Neuro1%2%ns0%2%0.024 HFS0%5%0.0015%0.5%0.004

19. Overall Survival 0.00 0.25 0.50 0.75 1.00 Overall Survival 0369121518 Time (Months) FU then OxFU 83 115 OxFU 81 115 Cap then OxCap 80 115 OxCap 84 115 Events Total Addition of oxaliplatin [FU vs OxFU] + [Cap vs OxCap] HR=0.94; p=0.61 Substitution of FU with Cap [FU vs Cap] + [OxFU vs OxCap] HR=1.00; p=0.97 ABCDABCD

20. Conclusions Elderly and frail advanced CRC patients: Can successfully be studied in a large RCT Despite similar RR, have markedly reduced median OS compared with standard RCT populations. The strategy of starting at 80% standard doses appears successful: Toxicity comparable with 100% dose in standard RCT populations 30-50% patients escalate to 100% at 6 wks Planned analyses of baseline comprehensive geriatric assessment will look for correlations with outcomes.

21. Conclusions Substituting capecitabine for FU in this population Had no major impact on global QL changes at 12 weeks, but slightly reduced the rate of improvement in overall/motility ADL scores. Had no detectable effect on PFS, RR or OS Produced significantly higher rates of grade ≥3 toxicity overall and specifically nausea, diarrhoea, lethargy and HFS. …but avoided the need for indwelling venous access.

22. Conclusions Adding oxaliplatin to fluoropyrimidine therapy in this population Had a non-significant impact on PFS (HR=0.83; p=0.06), with no impact on OS, despite a significantly improved RR. Did not increase overall rate of grade ≥3 toxicity, but significantly increased diarrhoea and peripheral neuropathy Reduced our ability to dose-escalate, and reduced the proportion of patients reporting improved QL at 12 weeks.