Adjuvant therapy in stage III colorectal cancer; Is less, better?

1. Adjuvant therapy in stage III colorectal cancer;Is less, better? Ioannis P. Boukovinas MD, PhD,PharmaD Medical Oncologist Bioclinic Thessaloniki ibouk@otenet.gr

2. Conflict of interest • Nothing to declare concerning this talk

6. X-ACT trial : Capecitabinevs5FU/LV as adjuvant in CRC (n=1987) Twelves C et al. N EnglJ Med 2005;352:2696-2704.

14. Could CapOx be more effective over 3 months than FOLFOX? Yes • Continous exposure to 5FU improves efficacy • Increased early oxaliplatin dosing? • In the first 4 weeks, the dose of oxaliplatin received is 260mg/m2 with CAPOX vs 170mg/m2 with FOLFOX • No • No obvious differences in metastatic CRC • The differences are due to patient selection: more favorable patients in CAPOX cohorts? Minimal difference in dose intensity by chemotherapeutic regimen

21. DFS by risk group and duration of therapy

22. Effect of T stage for N1 and N2 patients combined

23. Summary of IDEA results

24. Summary of IDEA results

26. Are there any clinical implications and for whom? For patients: Yes! Neuropathy measured by patient questionnaire over time by treatment duration SCOT trial, Iveson et al ASCO 2017

27. IDEA: Adverse events 3 vs 6 months • NEURO 2 to 6 times lower • DIARRHEA 20% to 30% lower • MUCOSITIS 2 times lower • H+F SYN 2 to 3times lower

28. Are there any clinical implications and for whom? For healthcare resource allocation: Yes! • Savings from 3 months rather than 6 months chemo: More than half a billion Euros saving per annum if every stage 3 CRC patient in Europe has 3 months CAPOX rather than 6 months chemotherapy • In Greece a rough estimation is 750 patients stage III/annum x 5000 Euros=3.500.000Euros savings/year The cost of 6 months therapy using CAPOX was £10,514 per patient versus £11,461 for FOLFOX. (NICE) 446,800 CRC pts diagnosed in 2012 in Europe, worldwide 1,360,602 (globocan) 25% stage 3: 111,700 in EU, @ £5257 saving per case = £587,206,900 per annum saving to health care system

30. What will I do with my next patient? • I will offer all my patients with T1-3/N1 3 months CAPOX as standard. • For high risk patients( T4) or who are unfit for CapOx(renal impairment), or those not tolerating CapOx, and therefore requiring FOLFOX, I will advise 6 months • For (fighter) patients with T4 or N2disease I will discuss the question of uncertainty of additional benefit of 3 extra months chemo. • However, toxicity and low cost effectiveness will make this option unattractive vs the revised 3 month standard.

31. For FOLFOX users.. Is this strong enough data to switch to CapOx? • FOLFOX v CapOx was not a randomized comparison • However, outcomes are highly comparable (3 yrDFS 76% from 6 mo FOLFOX v 75.9% 3 months CAPOX) • Strong toxicity and health economic drivers to use 3 months CapOx So Yes, I would switch to 3 months CapOx • If you cannot or will not switch to CapOx, then can you use 3 months? - No , it is inferior and risks losing much of the benefit of adding oxaliplatin to Fp.

32. Are there unanswered questions? • How do borderline fit patients fare in the trials? - Patients with GFR50-80 ml/min? increased capecitabine toxicity? - Older patients with high risk disease? • How does MSI status affect the outcome? • Is 3 months CapOx non- inferior to 6 months FOLFOX? - But I don’t think any funder will support this trial. • How can we identify stage 3 patients who need NO adjuvant chemotherapy? • How can we improve on oxaliplatin- based adjuvant chemotherapy? • Is there more effective therapy for T4 disease?

33. The findings of the IDEA collaboration provide useful information in helping oncologists discuss the duration of adjuvant therapy that best suits the goals, preferences, and tolerances of their patients.