Discrepant issues in the treatment of colon cancer Eric Rullier Deparment of Surgery University Victor Segalen of Bordeaux France Moscow, April 5-6, 2012

Treatment of colon cancer Staging Surgical technique Strategies Adjuvant treatment

Discrepancies in Surgical Techniques Colon cancer Discrepancies in Surgical Techniques

1329 patients 5-year survival 1978-1984 82% 1985-1994 84% 1995-2002 89%

Plane of dissection in 399 colonic specimens 1997-2002, Leeds Muscularis propria 24% Intramesocolic 44% Mesocolic 32%

Plane of dissection and type of colectomy

Complete Mesocolic Excision improves survival All patients Stage III

How to explain the better results?

Complete Mesocolic Excision (CME) Technical insufficiency issue More frequent in right colectomy Impact of extended lymphadenectomy vs. CME ? Novel concept or standardization of an old technique !?

Discrepancies in modern surgical techniques Colon cancer Discrepancies in modern surgical techniques

First acceptation of laparoscopic colectomy 2004 US COST

Barcelona, COST, COLOR, CLASICC

International guidelines Laparoscopic surgery is recommended for colon cancer US UK France Europe Asia Australia …since 2005 !

Contradiction Patients excluded from trials Obstruction, perforation T4, size > 6 cm Transverse, splenic flexure location Polyposis, IBD Previous laparotomy, BMI > 30 Surgeons excluded from trials < 20 or 30 previous laparoscopic procedures Leung Lancet 2004, COST NEJM 2004, COLOR Lancet Oncol 2005, CLASICC Lancet 2005

Reality: Colorectal Surgery in France 2010 National Database: PMSI 67 516 procedures 75% colon 25% rectum

Place of laparoscopy in colorectal surgery in France: 40%

Proportion of laparoscopy according to type of colectomy

Complexity and type of surgery Difficulty score and surgical procedure Colectomy TME Jamali FR et al. Arch Surg 2008

Impact of experience on conversion & mortality Evidence based Converted Not converted National trials Mid experienced surgeons CLASICC 2005 34% 9% 1% Single centers High experienced surgeons Braga DCR 2007 7% 1% 1% Luga BJS 2009 8% 3% 2%

Perspectives for laparoscopic colectomy Good indications T1-T3NxMx colon cancer Right & left location Educated and experienced surgeon in laparoscopy and colorectal surgery Relative indications T4 colon cancer Transverse location BMI > 30 Expert lap surgeon with high volume of cases

Discrepancies in ultra modern surgical techniques Colon cancer Discrepancies in ultra modern surgical techniques

Robotic Surgery

Current status of robotic colorectal surgery Two meta-analysis (Maeso S, Ann Surg 2010) (Mirnezami AH, Colorectal Dis2010) Five controlled, non-randomized studies: (Spinoglio G, 2008) (Woeste G, 2005) (D’Annibale A, 2004) (Anvari M, 2004) (Delaney CP, 2003) focused on colorectal resection included several diseases and surgical procedures Feasibility and Safety (Maeso S, Ann Surg 2010) Rob vs. Lap Surgical procedure Open conversion ↓ 4% Blood loss NS Morbidity Quality of specimen resection Resection margin Lymph nodes

Preliminary conclusion of robotic surgery Clinical advantages difficult to find in colorectal Probably impossible without experience At least 1 case a week necessary Advantages must be point out Patient: selected cases (obese, T4?) Surgeon: less stess Education: easier than laparoscopy Institution: Marketing +++ Limitations Lack of tactile and tensile feedback

Discrepant issues in surgical techniques Complete Mesorectal Excision New concept or standardization of surgery ? Laparoscopic colorectal surgery In selected patients for selected experienced surgeons In all patients for high volume expert surgeons Single Port and Robot The futur or the past ? Evidenced based is necessary

Discrepant strategies Advanced complicated disease Colon cancer Discrepant strategies Advanced complicated disease

Large bowel obstruction 20% of patients with colon cancer presented with bowel obstruction No recommandation for treatment Surgical options Colostomy then colectomy Hartmann then redo anastomosis Total colectomy High morbidity & stoma rates BJM

New option for obstruction: colonic stenting International registry 182 patients 98% technical success 94% clinical success Complications 8% Perforation 3% Migration 1% Obstruction 3% Bleeding 1% Jimenez-Perez J et al. Am J Gastroenterol 2011 (Dec)

Multicenter French Colonic Stenting Trial Stent Surgery (n=30) (n=30) Colostomy 13 17 0.30 Technical failure 16 (53%) Perforation 3 Premature closure of the study (n=80)

No data about long term oncologic outcome - perforation ? - tumor compression ?

Colonic stenting: perspectives New randomized trials ongoing (UK) Better selection Patient selection (M0 vs M1) Tumour location (left colon vs rectum) Impact on chemotherapy Interval between stent & surgery Design of the stent

Discrepant strategies Early colon cancer

Polypectomy vs. Colectomy in T1 colon cancer

Lymph node metastases in degenerated polyps 10-15% 27% Hagitt et al

Risk factors of lymph node metastases in T1 colon cancer 7543 patients treated by colectomy for cancer Incidence of T1= 8.6% Rate of N+ = 13% Predictive factors of N+ Sm3 Lymphovascular invasion Poor differentiation Nascimbeni R et al. Dis Colon Rectum 2002

Standard for colectomy in T1 Sm2 or Sm3 Lympho vascular invasion Poor differentiation Residual disease (margin < 1 mm)

What is new: balance strategy Retrospective study 2000 to 2010 64 patients with colectomy for unfavorable histology Definitions Oncologic risk: rate of N+ or R1 Operative risk: severe complication grade III-IV or death Aim : to analyse the correlation between the oncologic and the operative risks Benizri EL Int J Colorectal Dis 2012

Balance strategy for T1 colon cancer 64 colectomies Oncologic risk 11% 7.8% N+ 3.1% R1 Operative risk 13% 12.5% grade III-IV 0 death Oncologic benefit only if ≥ 2 histologic criteria Benizri EL Int J Colorectal Dis 2012

Conclusion controversy for T1 colon cancer Guidelines Taking account the oncologic risk Colectomy if 1 unfavorable histologic criteria Reality Taking account both the oncologic and the operative risks Colectomy if 2 unfavorable histologic criteria ?

Discrepancies in adjuvant treatments Colon cancer Discrepancies in adjuvant treatments

New classification of colon cancers TNM 7th edition (2009)

43 032 patients with colon cancer stage II & III Definition of stage II poor prognosis Bowel obstruction Bowel perforation T4 stage Lympho-vascular invasion

Stage II Poor prognosis Stage III

Adjuvant chemotherapy for colon cancer Evidence based for Stage III (6 m Folfox) Challenges for stage II Risk-benefice ratio unfavorable in all stage II Discrepant results in poor stage II Futur: new markers: RER & genetic signatures Challenges in old patients Older than 75y or with comorbidities Optimal CT : FU alone vs Folfox ?

FOXTROT UK trial

Coordonnateur : Pr Mehdi KAROUI (Chirurgien – Paris La Pitié) PRODIGE 22 – ECKINOXE Phase II randomisée : chimiothérapie néo-adjuvante par FOLFOX-4 avec ou sans Cetuximab vs chirurgie d’emblée dans le cancer colique localement avancé n° Eudract: 2011- 001519-29 – N° promoteur: P 100131 Essai intergroupe: AERO, FFCD, UNICANCER, FRENCH, GRECCAR Coordonnateur  : Pr Mehdi KAROUI (Chirurgien – Paris La Pitié) 63 v1.3 - 7.12.2011

STUDY DESIGN Randomisation stratifiée sur : centre investigateur 64 STUDY DESIGN 15 jours 3 à 5 semaines 3 à 5 semaines FOLFOX-4 (4 cures) ARM A Surgery FOLFOX-4 (8 cures) R FOLFOX-4 - cetuximab (8 cures) FOLFOX-4 - cetuximab (4 cures) Surgery ARM B (KRAS non muté) Surgery FOLFOX-4 (12 cures) ARM C 15 jours Randomisation stratifiée sur : centre investigateur stade ctT (T1-2-3 vs T4) sur scanner initial stade ctN (N0-N1 vs N2) sur scanner initial Et selon le statut K-ras : KRAS non muté (WT) : bras A, bras B, bras C KRAS muté : bras A et C v1.2 - 7.12.2011

New perspectives in adjuvant chemotherapy for colon cancer Neoadjuvant vs. adjuvant chemotherapy Two national trials Foxtrot UK trial Echinoxe F trial

Discrepant issues in treatment of colon cancer Conclusion CME: a new old concept = standardization Laparoscopy: experienced and high volumes teams increase laparoscopic cases Single port & Robot: a new challenge Obstruction: stent only palliative cases T1: apply guidelines but remember the patient ChemoT: the futur is treatment before surgery