Rectal Cancer : Curative treatment without surgery

Rectal Cancer : Curative treatment without surgery Dieter Hahnloser dieter.hahnloser@chuv.ch CHUV University Hospital Lausanne Switzerland

Reasons for intervention (surgery) Cure Live longer Feel better

CRM (Circumferential Resection Margin) Local recurrence Birbeck KF. Ann Surg 2002

CRM predicts outcome LR Mets 5yrsSV CRM pos 22% 40% 40% CRM neg 5% 12% 80% Wibe A. BJS 2002 LR overall SV CRM pos 23.7% 44.5% CRM neg 8.9% 66.7% Bernstein BJS 2009

Predicting CRM CT MRI

Predicting CRM CRM 4 mm CRM 10 mm

Radiotherapy influences CRM Bujko K. BJS 2006 312 pts, TME follow-up: 4 yrs 5x5 GY 50.4Gy +5-FU CRM pos 12.9% 4.4% pcr 0.7% 16% Sphincter- Preservation 61.2% 58.0%

CRM >1mm is ok Local Recurrence CRM 0-1mm CRM >1mm NCCTG 25% 3% Bernick P. Surg Oncl Clin N Amer 2000 CLASSIC 23% 9% Quirke P. LJ Pathol 2005

CRM = Pathology

CRM is most important! If CRM not compromised: Surgery! If ut1: Local excision possible

Single Port Transanal Surgery SPTS

Single Port Transanal Surgery SPTS

Single Port Transanal Surgery USZ/CHUV, Italy, Spain n=75 100% succesfull 8% fragmentation (all benign lesions) 8mm safety margins, all R0 Hopsital stay 3.4 days (1-21) SPTS 20% complications (14/15 patients grade I and II, one reoperation) Vaizey incontinence score 1 (1-4) at 310days (15-884) follow-up Hahnloser D. (submitted)

Recurrence-free survival N=224 TEM, 20 centres UK + Belgium Bach SP. BJS 2009

T1 rectal cancer: N+? Low risk High risk 4-7% 24-75% Using St Marks LN Positivity Model Tytherleigh MG/ Mortensen NJM. BJS 2008

T1Nx high risk T2Nx and now?

Immediate Radical Resection after Local Excision : a compromise? 100% 90% 80% 70% p=0.9 p=0.3 60% 50% 40% 30% 20% 10% T1N0-1 Cases (n=37) Primary radical surgery control (n=78) Local excision only control (n=77) Hahnloser D. DCR 2005 0 0 60 120 month after surgery

TME (Total Mesorectal Excision)

TME (Total Mesorectal Excision)

TME (Total Mesorectal Excision)

COLOR II Short Term Oncologic Endpoints Lap Open P CRM 1.3 cm 1.3 cm 0.16 Distal margin 3.6 cm 3.6 cm 0.68 Lymph Nodes 13 14 0.085 CRM < 2mm 9% 10% 0.78 Upper 10% 9% 0.92 Middle 9% 3% 0.073 Lower 9% 21% 0.013 van der Pas. Lancet Oncol 2013.

Platform for Teaching

Séreuse en jaune au niveau de la face antérieure Face antérieure en noir Face postérieure, en vert

muqueuse Séreuse (encré en jaune)

Can oncologic outcomes be improved with robotic surgery? Improvement in quality of mesorectal specimen (scored by pathologist with no clinical information) Baik SH et al, ASO 2009; 16:1480-7

Surgery for Rectal cancer 2013 If CRM not compromised: Surgery! If ut1: Local excision possible If ut2-3: TME Risk factors: T3b (>5mm EMD), extramural venous invasion T3b vs. T3a regardless N(!): 26% vs. 10% LR Merkel S. Int J colorectal Dis 2001 54% vs. 85% DFS

Surgery for Rectal cancer 2013 If CRM not compromised: Surgery! If ut1: Local excision possible If ut2-3: TME (if T3a, V0)

Surgery for Rectal cancer 2013 If CRM not compromised: Surgery! If CRM compromised: CRT

German Trial German Rectal Cancer Study Group 11yrs Folow-up J Clin Oncol 2012

15-30% no residual disease Complete Pathological Response To Neoadjuvant Chemoradiotherapy Study n= Interval to surgery cpr rate (weeks) EORTC 1011 5 13.7% EXPERT 77 6 24% CORE 85 6-8 13% RTOG 106 7 26% ypt0 ypn0 M0

Is histological response really a trustworthy surrogate marker for survival of the patient, or is it just a nice finding for surgeons and pathologists? «.it is a pcr, what a great job, we got it all out!»

pcr Local recurrence 0.7% Distant failure 8.7% 5yrs SV 90.2% DFS 87.0% 26 month median Adj chemo? 16 studies, n=3363 patients (1263 with pcr = 24.4% and 2100 without), FU 55.5 (40 87) months Martin ST. BJS 2012

Implications of pcr How to increase pcr? Less radical surgery? (organ sparing surgery) «Watch and wait»?

Aguilar JG. Ann Surg 2011 5-FU mfolfox-6 6 weeks 18% pcr 11 weeks 25% pcr same R0 rate, sphincter preservation, CRT toxicity increased fibrosis but same morbidity of surgery

Wolthuis AM. Ann Surg Oncol 2012 7 weeks 16% pcr >7 weeks 21% pcr N=356 stage II and III mid and distal rectal cancer 45 Gy + 5-FU, 4.9yrs FU

Wolthuis AM. Ann Surg Oncol 2012 N=356 stage II and III mid and distal rectal cancer 45 Gy + 5-FU, 4.9yrs FU

Predicting pcr? EUS CT PET MRI Tumour Fibrosis Rectal Wall

Local excision after CRT? SPTS

Local excision after CRT? Author Year pcr (%) Recurrence (%) SV (%) Mohiuddin 94 18T2 30T3 30 10 83 Kim 02 26T2&3 73 4 92 Ruo 02 6T2 4T3 30 20 78 Bonnen 05 26T3 54 11 86 Lezoche 11 84T2 29 5 93 Z6401 trial 11 77T2 44 n/a n/a

T2N0 TEM vs. TME TEM TME p-value ypt0 28% 26% 0.89 OR time (min) 90 174 0.001 N receiving transfusion 0 20% 0.001 Hospital stay (d) 3 6 0.001 N=50:50, all T2N0, <3cm, within 6cm from AV, all neoadjuvant radiochemo Lezoche G. BJS 2012

T2N0 TEM vs. TME Recurrence (local + distant) Disease-free survival TEM TME TEM TME N=50:50, all T2N0, <3cm, within 6cm from AV, all neoadjuvant radiochemo Lezoche G. BJS 2012

Local excision reliable for identifying residual disease? 9.2% 7% 2% 2% 18.6% 8% 4% 15% 21.8% 22% 23% 17% 48.2% 37% 47% 38% 43.7% 67% 48% 33% Chang GJ. ASCO 2011 Stipa F. Ann Surg Oncol 2004 Read TE. DCR 2004 Pucciarelli S. Ann Surg Oncol 2005 Courtesy of Chang GJ.

Recurrence Free Survival Recurrence Free Survival Recurrence Free Survival Recurrence Free Survival Impact of TME on disease control with node positive disease A A 1.0 B B 1.0 0.8 0.6 0.8 P=0.28 P=.25 0.6 P=.005 P=0.010 0.4 0.4 0.2 0.0 ypt0-2n+ N + ypt0-2n0 N - 0 24 48 72 96 Month after Surgery Months After Surgery 0.2 0.0 ypt3-4n+ N + ypt3-4n0 N - 0 24 48 72 96 Months after Surgery Months After Surgery Park et al, ASCRS 2012 Courtesy of Chang GJ.

clinical Complete Response (ccr) Whitening : ok Teleangiectasia: ok Loss of pliability of rectum (insufflation): ok No palpable ulcer/nodule/mass No radiological evidence of extrarectsl disease Habr-Gama A. DCR 2010

Habr-Gama A. Ann Surg 2004 CLINICAL n (%) Complete 71 (26.8) Incomplete 194 (73.2) PATHOLOGIC n (%) yp0 22 (8.3) ypi 61 (23) ypii 70 (26.4) ypiii 41 (15.5) All rectal cancers 0-7 cm eligible No adjuvant chemotherapy f/u 12-156 months 2 (2.8%) late endoluminal recurrences (56 & 64 mos.) 3 (4.2%) systemic metastases

ccr 21 days 6 weeks 9 weeks 54Gy + 5-FU based chemo x6 2006-2011, >7cm from AV, ct2-4 n0-2 M0, median FU 53 month Habr-Gama A. presented @ ASCRS 2013 47 (68%) ccr 100% salvaged =62 (51%) non-operative managment 94% overall SV, 75% DFS 8(17%) early re-growth median 7m 4(10%) late recurrence median 21m = Local failure 12 (27%)

Watch and wait? NOM: no palpable mass, scarr on endoscopy NOM significant older, more pretreatment morbidity, less stage III NOM 21% LR (11months): 100% salvage surgery 81% in NOM avoided surgery NOM n=32, median FU 28month vs 57/265 (22%) pcr Smith JD. Ann Surg 2012

Watch and wait? Local failure Habr- Gama: 3-6% Non Habr-Gama: 33.8% (n=289 patients) Modern studies with systematic FU: 29% (n=92p) Review n=18 Habr-Gama, n=12 non Habr -Gama Glynne-Jones R. BJS 2012

Problem: assessing ccr Criteria + timing heterogenous ypt0 correlates partially with N0 (N+ 5-10%) Size of LN poor predictor. 50% N+ <3mm Perez RO. DCR 2009 MRI? mrtrg good response: 72% vs. 27% 5yrs SV DFS 64% vs. 31% Mercurry study Patel UB J Clin Oncol 2011 PET-CT? Variation SUV baseline-12 weeks : >76% ccr (Sensitivity/specificity > 70/80%) Perez RO. Presented @ ASCRS 2013

Problem: assessing ccr ccr correlates poorly with pcr 50% pcr did not have complete ccr Residual mucosal abnormalities <3cm associated with ypt0-1 and <2% N+ Smith FM BJS 2012 Local excison after CRT possible: pcr 45% (3-73), LR 5% (0-23) but might compromises sphincter-saving surgery Studies ongoing (CARTS, ACOSOG Z6041)

Surgery for Rectal cancer 2013 If CRM not compromised: Surgery! If CRM compromised: CRT @6weeks: ccr? Interval to TME? Discuss local excision, watch and wait (studies!) TME (lap, robotic)

Rectal Cancer: Curative treatment without surgery Not yet Tailored surgery Later? Different? (local excision) but quality controlled