TARMKRÆFTKONFERENCE. Onsdag, d. 21. marts 2018, kl ca Kræftens Bekæmpelse, Strandboulevarden 49, 2100 København Ø

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1 Vers TARMKRÆFTKONFERENCE Onsdag, d. 21. marts 2018, kl ca Kræftens Bekæmpelse, Strandboulevarden 49, 2100 København Ø Tarmkræftpatienter behøver kun halvt så meget kemobehandling som tidligere Niels Henrik Holländer Sjællands Universitetshospital (SUH)

2 Indhold Inter Reg Danmark-Tyskland finansieringskilden KFFB.EU InnoCan.org Stadieinddeling og klassifikation SCOT randomiserede ptt. IDEA randomiserede ptt. Dansk opfølgning i Trans SCOT Tids SCOT / TIDS IDEA Publikationsplaner

3 InnoCan = Innovative High Technology Cancer Treatment Denmark-Germany

4 Lead partner: Project partners: DK DE Network partners: DE DK 01 Sjællands Universitetshospital, Onkologi (SUH, Lead partner) 02 Region Sjælland, Produktion, Forskning og Innovation (PFI) 03 Odense Universitetshospital (OUH) 04 University College Sjælland (UCSJ) 05 Designskolen Kolding (DSK) 06 Cortrium ApS 07 Kræftens Bekæmpelse (KB) 08 Universität zu Lübeck (UKSH) 09 Universität Kiel (UKSH) 10 Krebsregister Schleswig-Holstein (IKE) 1 Wirtschaftsförderung u.technologietransfer Schleswig-Holstein (WTSH) 2 Life Science Nord, Hamburg 3 Philips (Holland) 4 Welfare Tech, København

5 Projekt periode Budget DKK Euro Projekt budget i alt (ca. 60%)

6 InnoCan vil forbedre, forenkle og forkorte kræ-behandling ved: at teste nye teknologier at udvikle et testcenter, som skal hjælpe virksomheder på markedet med deres sundhedsteknologier at forske i mere skånsom behandling af brystkræt, tarmkræt, hoved og halskræt, prostatakræt, rygmarvskompression og kræt hos ældre at samle og sammenligne danske og tyske bedre forskning gennem et fortsat samarbejde mellem to krætregistre i DK og D (kvalitetskontrol).

7 , EU Interreg 4a Budget i alt: 10,4 mio. kroner Næstved Sygehus Universitetsklinik Schleswig-Holstein, Lübeck

8 Highlights af KFFB samarbejdet Deltagelse i et internationalt kræftforskningsstudie (SCOT), hvor Danmark blev den 3. største bidragsyder ASCO Annual Meeting 2015, J. Clin. Oncol. 33, 2015 (suppl; abstr 3514) og ASCO 2017 Ny viden fra samarbejdet mellem kræftregistrene (Danmark og Schleswig- Holstein). Vigtig grundlag for forbedringer af behandling og fremtidig forskning. Flere intern. videnskabelige publikationer Forskellig organisering af kræftbehandlingen i begge regioner. Stor velvilje af alle faggrupper at lære fra hinanden. Letter of Interest, Samarbejde Universitet Lübeck- Københavns Universitet - Region Sjælland Honorarprofessorat KU og tyske lægestuderende (famulatur)

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12 Final DFS results of the SCOT study: An International Phase III Randomised (1:1) Noninferiority Trial Comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer Timothy Iveson, Rachel S Kerr, Mark P Saunders, Niels Henrik Hollander, Josep Tabernero, Andrew Haydon, Bengt Glimelius, Andrea Harkin, Claire Scudder, Kathleen Anne Boyd, Ashita Waterson, Louise Medley, Charles Wilson, Richard Ellis, Sharadah Essapen, Amandeep S Dhadda, Mark Harrison, Stephen Falk, Sherif Raouf, James Paul

13 SCOT endpoints Primary endpoint DFS (time from randomisation to relapse, development of new colorectal cancer or death) Secondary endpoints Toxicity Quality of Life Health economics Overall survival

14 SCOT Design High risk stage II or stage III cancer of the colon or rectum Selection of adjuvant CAPOX or FOLFOX (patient/ physician choice) R 3 months duration 6 months duration

15 Statistical design Non-inferiority Designed as a non-inferiority trial aiming to exclude a maximum 2.5% fall in 3-year DFS on the 3 month arm corresponding to a hazard ratio of 1.13 Power For a hazard ratio of 1.13 and 90% power at the 2.5% 1- sided level of statistical significance, 9500 patients and 2750 events needed

16 Results: SCOT recruitment Recruitment between 27 th March 2008 and 29 th November 2013 Country Patients Centres UK Denmark Spain Australia Sweden New Zealand 16 5 Total

17 SCOT CONSORT Diagram Randomized (n=6088) Allocated to 3 months treatment (n=3044) 9 patients withdrew consent for use of on study data Patients with consent to use data (n=3035) Allocation Allocated to 6 months treatment (n=3044) 14 patients withdrew consent for use of on study data Patients with consent to use data (n=3030) Started study treatment (n=3009) Treatment Started study treatment (n=3013) Follow-up on 3035 patients Ef,icacy Analysis Disease-free and overall survival Follow-up on 3030 patients ITT analysis: all randomized pts who did not withdraw consent for data to be used Presented by:tim Iveson, MD on behalf of SCOT investigators

18 Results: Patient characteristics 3 months 6 months Gender Female 39.5% 39.4% Male 60.5% 60.6% PS % 70.4% % 29.6% Site Colon 81.9% 82.0% Rectum 18.1% 18.0% Age Median (IQ range) 65 (58-70) 65 (58-70)

19 Results: Patient characteristics 3 months 6 months T stage 0 0.0% 0.1% 1 3.0% 3.1% 2 9.3% 9.3% % 57.4% % 30.1% N stage % 18.3% % 56.9% % 24.8%

20 Results: Treatment regimen Regimen 3 month duration 6 month duration CAPOX 2051 (67.4%) 2056 (67.5%) FOLFOX 993 (32.6%) 988 (32.5%)

21 Results: Treatment compliance Percentage of full oxaliplatin and full fluoropyrimidine dose by randomised study arm and initial treatment choice 98% 94% 85% 82% 98% 96% 73% 69% Figures beside boxplots indicate the median percentage full dose

22 Results: Grade 3/4 adverse events by Duration and Regimen

23 Results: Neuropathy measured by patient questionnaire over time by treatment duration Months from randomisation Years from randomisation

24 Results: DFS Overall Population Total number of events= 1482 giving 66% power Percentage of patients alive and disease free 100 % 90 % 80 % 70 % 60 % 50 % 40 % 30 % 20 % 10 % 0 % iarm 3 months 3 (n=3035, treatment events=740) 6 months 6 (n=3030, treatment events=742) Arm 3-yr DFS (95% CI) HR (95% CI) Non-inferiority p-value 3m 76.7% (75.2%-78.2%) ( ) m 77.1% (75.6% -78.7%) Ref 3yr DFS difference = -0.4% (-2.6% to 1.8%) Number at risk: Time from randomisation (years) 3 months: months:

25 Results: DFS duration comparison by N- and T- Stage Variable T-stage p= N-stage p= Category 1/ month arm Events/Patients 34 / / / / / / month arm Events/Patients 47 / / / / / / 754 3m better 6m better Noninferiority boundary Stage High risk stage II 99 / / 555 p= Stage III 641 / / 2472 Overall 740 / / 3030 P-values are for heterogeneity of the duration effect over the variable categories

26 Results: DFS duration comparison by adjuvant treatment and site of disease Variable Category Site p= Adj trt p= Colon Rectum FOLFOX CAPOX 3 month arm DFS/Patients 633 / / / / month arm DFS/Patients 628 / / / / m better 6m better Noninferiority boundary Overall 740 / / 3030 P-values are for heterogeneity of the duration effect over the variable categories Hazard ratio

27 Results: DFS by Regimen CAPOX (n=4092) FOLFOX (n=1973) Percentage of patients alive and disease free 100 % 95 % 90 % 85 % 80 % 75 % 70 % 65 % 60 % 55 % 50 % 45 % 40 % 35 % 30 % 25 % 20 % 15 % 10 % 5 % 0 % iarm 3 months 3 (n=2049, treatment events=491) months treatment 6 months 6 months (n=2043 treatment events=529) treatment Arm 3-yr DFS (95% CI) HR (95% CI) Non-inferiority p-value 3m 76.9% (75.0%-78.7%) 6m 76.1% (74.2% -78.0%) ( ) Ref 3yr DFS difference = 0.8% (-1.9% to 3.4%) Percentage of patients alive and disease free 100 % 95 % 90 % 85 % 80 % 75 % 70 % 65 % 60 % 55 % 50 % 45 % 40 % 35 % 30 % 25 % 20 % 15 % 10 % 5 % 0 % iarm iarm 3 months 3 months (n=986, treatment events=248) months treatment 6 months 6 months (n=987, treatment events=213) months treatment Arm 3-yr DFS (95% CI) HR (95% CI) Non-inferiority p-value 3m 76.4% (73.6%-79.1%) 6m 79.2% (76.6% -81.8%) ( ) Ref 3yr DFS difference = -2.8% (-6.6% to 0.9%) Time from randomisation (years) Number at risk: 3 m m Time from randomisation (years) Number at risk: 3 m m

28 Results: DFS by Stage III Risk Group Percentage of patients alive and disease free 100 % 95 % 90 % 85 % 80 % 75 % 70 % 65 % 60 % 55 % 50 % 45 % 40 % 35 % 30 % 25 % 20 % 15 % 10 % 5 % 0 % Number at risk: 3m 6m iarm 3 months 3 (n=1331, treatment events=202) 6 months months (n=1332, treatment events=223) 6 months treatment months treatment Arm 3-yr DFS (95% CI) HR (95% CI) Noninferiority p-value 3m 85.3% (82.5%-88.2%) ( ) 6m 84.0% (80.6%-87.4%) Ref T1-3/N1 (n=2663) 3yr DFS difference = 1.3% (-1.5% to 4.2%) Time from randomisation (years) iarm Percentage of patients alive and disease free 100 % 95 % 90 % 85 % 80 % 75 % 70 % 65 % 60 % 55 % 50 % 45 % 40 % 35 % 30 % 25 % 20 % 15 % 10 % 5 % 0 % Number at risk: 3m 6m iarm 3 months 3 (n=1143, treatment events=439) 3 months treatment 6 months 6 months (n=1140, treatment events=417) 6 months treatment Arm 3-yr DFS (95% CI) HR (95% Ci) Noninferiority p-value 3m 63.0% (59.9%-66.2%) ( ) 6m 64.9% (61.4%-68.4%) Ref T4 or N2 (n=2283) yr 2 DFS difference 3 = 4-1.9% (-5.9% 5 to 62.2%) Time from randomisation (years)

29 Results: DFS duration comparison by expanded stage Variable Expanded Stage p= Category High risk stage II Stage III (T1-3/N1) Stage III (T4 or N2) 3 month arm Events/Patients 99 / / / month arm Events/Patients 101 / / / m better 6m better Noninferiority boundary Overall 740 / / 3030 P-values are for heterogeneity of the duration effect over the variable categories Hazard ratio

30 Results: 3-year DFS by risk group and regimen Risk Group T1-3,N1 T4 or N2 Regimen 3-yr DFS Difference (95% CI) 3m minus 6m HR (95% CI) 3m versus 6m CAPOX (n=1774) 3.4% ( 0.1%, 6.9%) 0.76 ( ) FOLFOX (n=889) 2.9% ( 7.7%, 1.9%) 1.27 ( ) CAPOX (n=1515) 1.4% ( 6.4%, 3.6%) 1.05 ( ) FOLFOX (n=768) 2.7% ( 9.6%, 4.1%) 1.13 ( )

31 Summary SCOT met its primary endpoint showing that DFS with 3 months adjuvant chemotherapy is noninferior to 6 months treatment in the total overall population

32 Summary: Choice of regimen The choice of regimen appears important CAPOX; 3 months treatment was as good as 6 months treatment FOLFOX; did not meet criteria for non-inferiority

33 Summary: Prognostic Groups Low-risk stage III disease (T1-3,N1) 3 months treatment was as good at 6 months treatment High risk stage III disease (T4 or N2) did not meet non-inferiority criteria

34 Conclusions Overall SCOT met its non-inferiority target for 3 months of adjuvant chemotherapy and 3 months treatment should be considered for some patients Patients with high risk stage III disease should be counselled regarding absolute difference in survival and risk of increased toxicity with 6 months treatment

35 Acknowledgements The SCOT Trial Team would like to thank: All patients and their families who took part in SCOT All Investigators and site staff across all the contributing countries The International Collaborative Groups who led the trial in their countries: The Danish Colorectal Oncology Group Vall d Hebron University Hospital and Institute Oncology (VHIO), Universitat Autònoma de Australasian Gastro-Intestinal Trials Group (AGITG) Swedish Society of Gastrointestinal Oncology of Barcelona

36 Acknowledgements This study was Co-Sponsored by: NHS Greater Glasgow and Clyde Health Board and the University of Glasgow This study was funded by: an MRC and NIHR partnership created to support the evaluation of interventions with potential to make a step-change in the promotion of health, treatment of disease and improvement of rehabilitation or long-term care Cancer Research UK Core Clinical Trials Unit funding (Glasgow)

37 Acknowledgments The SCOT Trial Team would like to thank: The Cancer Research UK Clinical Trials Unit in Glasgow who led the trial within the UK and Internationally The Oxford Oncology Trials Unit (OCTO) who managed 80/163 UK sites Professor Jim Cassidy who initiated this research during his time at the University of Glasgow All other authors

38 Prospective Pooled Analysis of Six Phase III Trials Investigating Duration of Adjuvant Oxaliplatin-based therapy (3 vs. 6 months) for Patients with Stage III Colon Cancer: <br />The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration Presented By Qian Shi at 2017 ASCO Annual Meeting

39 International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration Presented By Qian Shi at 2017 ASCO Annual Meeting

40 Background and Rationale Presented By Qian Shi at 2017 ASCO Annual Meeting

41 Study Overview Presented By Qian Shi at 2017 ASCO Annual Meeting

42 Study Schema Presented By Qian Shi at 2017 ASCO Annual Meeting

43 IDEA Trials Summary Presented By Qian Shi at 2017 ASCO Annual Meeting

44 Summary Presented By Qian Shi at 2017 ASCO Annual Meeting

45 IDEA Clinical Consensus: Risk-based approach to adjuvant chemotherapy in stage III colon cancer Presented By Qian Shi at 2017 ASCO Annual Meeting

46 Dansk Opfølgning på SCOT Deltager i Trans SCOT Estrid Høgsdal og Prof. Ismail Gögenur sidder begge i styregruppen. Tids SCOT Kan tiden fra operation til start på kemoterapien korreleres til forskelle i outcome. Sammen med Prof. Ismail Gögenur undersøges de 6088 SCOT ptt. Om og evt senere de satdie III coloncancer ptt i IDEA

47 Publikationer Lancet Oncology SCOT main efficacy results but also the treatment toxicity and QoL data Cost effectiveness manuscript is submittet til EJC New England J. Medicine (NEJM) IDEA has been accepted for publication Posteres på ESMO og ASCO GI Ekstra Bladet!

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