Neoadjuvant treatment for all – what is the evidence? Prof. James N’Dow Chairman, EAU Guidelines Office No conflicts of interest FOIU: July 6th Hall A 9:40 – 9:50

Dr. Max Bruins

MIBC Guidelines Associate

EAU Guidelines Office

EAU Guidelines

• EAU Guidelines are becoming more influential as an

important tool to improve clinical care, unification of

healthcare provision and managing resources across

Europe

• Ensure a balanced view of risks and benefits (free of bias),

in which preferences of patients, clinical practice and

healthcare policy needs are matched with science

• Not yet well tailored to Individual patient care needs and

much work needed to impact shared decision-making

• The EAU Guidelines Office’s systematically introduced

Cochrane review methodology across all 20 Guideline

Panels

EAU Guidelines Office

Legal Implications of Guidelines –

EAU Guidelines Office Position

• Guideline recommendations are for Guidance only

• Recommendations are not very good at individualising care

So, practitioners must use best understanding of patient’s case to

decide whether application of the recommendation is appropriate

or not

Non-adherence to strong recommendations must be justifiable, for

example due to specific patient circumstances (justification &

informed consent must be documented in patient’s records)

• Systematic non-adherence to strong recommendations is

unwise

• Guidelines are NOT legally binding documents between

practitioner and patient

EAU Guidelines Office

Legal Implications of Guidelines –

TAKE HOME MESSAGE

• Guidelines will increasingly impact our practices (so ….. understand

& use them)

• Guidelines provide guidance only (to assist in shared decision making)

• Systematic non-adherence to strong recommendations could

leave you exposed legally

• Document in patient records credible reasons for non-

adherence to a strong recommendation

• Ask yourself if majority of your peers would agree with your

decision given the same circumstances

• Lawyers are increasingly likely to use Guidelines as evidence

EAU Guidelines Office

1. The Algerian Association of Urology

2. The Argentinian Society of Urology

3. The Armenian Association of Urology

4. The Austrian Urological Society

5. Urological Society of Australia and New Zealand

6. The Belarusian Association of Urology

7. Belgische Vereniging voor Urologie

8. The British Association of Urological Surgeons

9. La Sociedad Chilena de Urología

10. The Chinese Urological Association

11. La Sociedad Colombiana de Urología

12. The Cyprus Urological Association

13. The Czech Urological Society

14. The Dutch Association of Urology

15. European Association of Urology

16. The Estonian Urological Society

17. Association Française d'Urologie

18. The German Urological Association

19. The Georgian Association of Urology

20. The Hellenic Urological Association

21. The Hong Kong Urological Association

22. The Hungarian Urological Association

23. The Norwegian Urological Society

24. The Urological Society of India

25. The Indonesian Urological Association

26. The Irish Society of Urology

27. The Italian Association of Urology

28. The Kosova Urological Association

29. The Latvian Association of Urology

30. The Lithuanian Urological Society

31. The Macedonian Association of Urology

32. The Malaysian Urological Association

33. The Polish Urological Association

34. The Portuguese Urological Association

35. The Romanian Association of Urology

36. The Russian Society of Urology

37. Slovak Urological Society

38. The Slovenian Urological Association

39. The Spanish Association of Urology

40. The Swedish Urology Association

41. The Swiss Society of Urology

42. The Taiwan Urological Association

43. The Turkish Association of Urology

44. The Thai Urological Association

45. The Ukrainian Association of Urology

National Societies Endorsments

Treatment of muscle-invasive bladder cancer

• Gold standard treatment: radical cystectomy (RC)

• Oncological outcomes of RC with extended LND unchanged for 30 years1

- 5-year RFS overall ~ 67%

- 5 year RFS node-positive ~ 35%

• Low use of adjunct chemotherapy in Europe - Neo-adjuvant ~ 12% in 2012 2

- Adjuvant ~ 2-5% in 2012 3 (±20% in USA4)

1. Zehnder et al. BJUI 2013 2. Burger et al. Eur Urol 2012

3. Hermans et al. Eur J Cancer 2016

4. Reardon, Eur Urol 2015

Burning questions?

1. Does additional chemotherapy improve survival?

2. If yes, when to provide it?

OR

What does the EAU Guidelines say?

What is the evidence behind these recommendations?

• Published: 2003; recruited 1987 - 1998 • cT2-T4aN0 n=153: 3 x MVAC 28 days + cystectomy

n=154 cystectomy alone

• Endpoints: OS and downsizing (achieving pT0).

• 87 % completed at least 1 cycle of MVAC

• 37% grade IV adverse event (mostly granulocytopenia)

• No difference in Gr III-IV postoperative complications

• 5-year OS 57% MVAC/RC vs 43% RC alone (p= 0.06)

• pT0 response 38% MVAC/RC vs 15% RC alone

• RC rate 82% MVAC/RC vs 81% RC alone

• Time to RC 115 days MVAC/RC vs 17 days RC alone

• Published 2004

• Analysis of 2 Nordic Trials

• Total 620 eligible patients

• Patient included between 1985 – 1997

• OS 56% in NAC/RC vs 48% in RC only = 8% absolute risk reduction

• HR 0.80 (0.64-0.99) = 20% relative risk reduction

Meta-analysis for NAC

1. Abol-Enein et al. (Lancet 2003)

2. Winquist et al. (J Urol 2004)

3. Advanced bladder cancer meta-analysis collaboration (Eur Urol 2005)

• 3005 patients, 11 trials (comprising 98% of all RCT patients)

• Regimens: MVAC, MVA(E)C, CMV,CM, CA, C-5FU, Carbo-MV

• DFS: HR 0.78 (p<0.0001), 9% absolute improvement after 5 yrs

• OS: HR 0.86 (p=0.003), 5% absolute improvement after 5 yrs

Why Neoadjuvant?

Pros

• Burden of micrometastasic disease is low

• Better tolerability of chemotherapy pre-cystectomy

• Better patient compliance

• No negative impact on surgical morbidity

• No influence on cystectomy performance

• Higher LoE compared to adjuvant chemotherapy

Why Neoadjuvant?

Limitations:

• Overtreatment is a risk for some patients

• 5-8% survival benefit is limited

• Benefit demonstrated particularly in pts with high PS, good GFR and age <70

estimated 1/3 of bladder cancer patients do not fall in this category

• Prediction of responders remains challenging (? Biomakers)

Thank you