A.D’Hoore MD PhD, A. Wolthuis MD, F. Penninckx MD PhDK. Haustermans MD PhD*, E. Van Cutsem MD PhD**

V. Vandecaveye MD PhD***

Department of Abdominal Surgery, Radiation Oncology*,GI Oncology** and Radiology***

Catholic University of LeuvenBelgium

Organ sparing-strategy in rectal cancerImportance – How can we progress ?

Radical Surgery(TME +/- proctectomy)

Actual treatment in rectal cancer

Early rectal cancer(T1,T2,N0)

Advanced rectal cancer≥ T3, TxN1

Neoadjuvant (chemo)radiotherapy

TEM/TAE

T1sm1 < 3 cmgood-moderate differentiationabsence LV-invasionnon-ulcerated

Surgery is the main mechanism for cure in colo-rectal cancer

neo-adjuvant chemoradiation preferred strategy to further improve local control

Sauer R et al. N Engl J Med 2004; 351:1731-40.

Current strategy

neoadjuvant chemoradiation

radical surgery (TME) - risk for permanent stoma - deterioration of bowel function

increased risk surgical complications increased postop death rate (elderly) longterm impact anorectal/sexual function

Appeal of organ preservationMinimal perioperative morbidity and mortality

- bleeding- anastomotic leak

Rapid recoverySphincter saving operationPreservation of bowel function

- ‘anterior resection’ syndrome- permanent colostomy

Preservation of urogential functionImproved QoLReduction in Health care cost

Effect of neoadjuvant chemoradiation - improve local tumor control- tumor downsizing - cancer,nodal sterilization : 12 – 24%

complete pathologic responsecT3-T4

RT RT + 5-FU

Bosset JF et al J Clin Oncol 2005EORTC 22921

5.3% 13.7% p<0.0001

Gerard JP et al. J Clin Oncol 2006FFCD 9203

3.6% 11.4% p<0.05

Complete pathological response (pR) to neoadjuvant chemoradiotherapy

n patients Interval to surgery (weeks)

cPR rate (%)

EORTC 1011 5 13.7

EXPERT 77 6 24

CORE 85 6-8 13

RTOG 106 7 26

0S

DFS

n= 265 pts, distal rectal cancer

wait and seen = 71 pts (26.8%) sustained cCR

Local Excision:n = 22 pts(8.3%) pT0 ….observation

__ radical surgery

Ann Surg 2004;240(4):711-7

stratification at 8-10 weeks

Late recurrencesoverall : 21% (n=15)

n (%) Time to relapse(median,mo)

Local recurrence(all endoluminal !)

8 (11) 39 mo

all salvage therapy (1 late recurrence after APR)

Extra rectal pelvic 0

Distant metastasis 7 (10) 19 mo

Habr-Gama A et al. Semin Radiat Oncol 2011;21:234-239.

Nodal metastasis in relation to ypT

Read 2004 Bujko 2005 Guillem 2008 Mignanelli 2010

Wolthuis 20110

10

20

30

40

50

60

Background risk for untreated nodal disease

male, 57 yr.uT1 , 2 cm above anal verge

TAE : pT1 sm3, G2-3LV+, PN –

Adjuvant chemoradiation : 50.4 Gy, infusional 5 FU

Intensive FU : 5 yearsyearly endoscopy

at 9 years: sciatic pain +++

Actual series on non-operative treatment after chemoradiation and cCR

n cCR FU (mo) Local failure

Habr Gama 2006(1991-2005)

361 99 (27.4%) 60 5 (5.0%)

Habr Gama 2011(1991-2011)

173 67 (38.7%) 65 8 (11%)

Maas 2011 192 21 (10.9%) 25 1 (4.7%)

Yu 2011 22 17.8 9 (41%)

Dalton 2012 49 12 (24%) 25 6 (50%)

“wait and see protocols”

- lack of clarity to define clinical complete response (cCR)- clinical criteria- imaging- punch biopsy – TEM (excisional biopsy)

- 20% fail the first year (early failure)- outcome early salvage

- uncertainty in regard to long-term efficacy (late failure)- rational, consistent follow-up programme- selection of patients- outcome late salvage

Complete clinical response (Habr Gama)inter observer variablity ?

- careful digital examination

- proctoscopy- whitening of mucosa- teleangiectasia- loss of plicability of rectal wall

Habr-Gama et al. Dis of Colon Rectum 2010;53:1692-1698

Predictive value of clinical complete response (ccR)

n= 488 patients Memorial Sloan Kettering

ccR = 19%

cpR = 10%

ccR = predictive factor for cpR

but :

75% of ccR : residual foci of tumor:

Significance of residual mucosal abnormalities ?

61% (19/31) with cPR had an incomplete cR

ypT3N1

Smith FM et al. Br J Surg 2012; 99:993-1001

ypT0N0

ypT0N0

mucosal lesion

ypT0 ypT1

< 1cm 42% 27%

1-2cm 10% 9%

> 3cm 1% 0%

ypT0N0

Can biopsies rule out persisting cancer

in incomplete clinical response ?

PPV = 100% NPV = 21%accuracy = 71%

Perez RO et al. Colorectal Dis 2012

Transanal Endoscopic Microsurgery (TEM)

Buess G et al. Surg Endosc 1988; 2: 245- 250

Pooled data on TEM after neo-adjuvant chemoradiotherapy

LRR (%) MD (%)

yp T0 n = 53 22 % 0% 4%

yp T1 n = 45 19 % 2 % 7%

yp T2 n = 85 36 % 7% 7%

yp T3 n = 34 14 % 21% 12%

6 retrospective studies, 1 prospective studyBorschitz T et al. Ann Surg Oncol 2008;15:712-720

Morbidity TEM after neoadjuvant chemoradiation therapy

Study group (neoadjuvant

CRT)N=23

Control group

N = 13 p

Grade I morbidity 52% 13% 0.030

Grade II/III 56% 23% 0.050

Wound dehiscence

70% 23% 0.030

readmission 43% 7% 0.020

Interval to healing 8 (5-12) weeks

Perez RO et al. Dis Colon Rectum 2011; 54: 545-551

Maastricht (Dutch) criteria formultimodal assessment of response

-substantial downsizing: no residual tumor, only fibrosis(low signal on high b-value DW- MRI)

-no suspicious lymphnodes on MRI(USPIO, gadofosveset) contrast enhanced MRI

-no residual tumor at endoscopy (residual scar)

-normal biopsies from the scar

-no palpable tumor

Maas M. et al. J Clin Oncol 2011; 29:4633-4640

T2 – weighted MRI DWI- MRI pre post CRT post CRT

patient not eligible for wait and see

diagnostic performance of MRI for the prediction of complete response (ypT0)

Standard MRI MRI + DWISensitivity 0-40% 52-64%Specificity 92-98% 89-97%PPV 0-56% 62-81%NPV 79-85% 88-90%AUC 0.58-0.76 0.78-0.80*κ –IO agreement 0.2-0.32 0.51-0.58

Lambregts D et al. Ann Surg Oncol 2011

Pet-CT and clinical assessment

6 w

12wPerez RO et al. Cancer 2011

Radiation induced tumor downsizingis time-dependent

Dhadda A.S. Clinical Oncology 2009; 21:23-31

Improving local control in rectal cancer

Radio-chemotherapy

Radio-chemotherapy

Radio-chemotherapy

resting period

resting period

resting period resting periodchemotherapy

Higher radiation dose Increasing interval to surgeryEffective radiation sensitization Neoadjuvant chemotherapy

-S

-S

-S

Increasing the interval ?(n=48)< 7 w

(n=84)>7 w

pCR + near pCR 17% 35% p = 0.03DFS increased p = 0.05

Tulchinsky H et al. Surg Oncol 2008;15:2661-2667

Retrospective cohort analysis :length of interval and cPR and DFS

(Leuven rectal cancer database)

Interval (days)

≤ 7 weeks : median 44.0 d n=201 ypT0N0 : 16%

> 7 weeks : median 54.0 dn=155 ypT0N0 : 28% (p=0.006)

Accepted Ann Surg Oncol 2012

Additional chemotherapy during resting period

n %Initial CR 22 75.8Sustained CR 19 65.5Clinical assesment alone 14Full-thickness biopsy 5

Habr-Gama A. Dis Colon Rectum 2009;52(12):1927-1934

Advanced rectal cancer: nonrandomized phase II prospective trial

n=144

Radio-chemotherapy

Radio-chemotherapy

resting period

mFOLFOX6

-S 18%

-S 25%p=0.0217

pCR

Garcia-Anguilar J. Ann Surg 2011; 254:97-102

Timing of tumor assessmentat 12 w for every one ?

bad

good

Prediction ?

Perez RO et al. Int J Radiation Oncol Biol Phys 2012

multimodal defined complete clinical response

“wait and see” TAE/TEM(full-thickness local excision)

sustained cCR ypT0 yp≥T1

completion surgery (after 8 weeks)

stringent and prolonged FU

early failures

late failures

delayed radical surgery

Completion radical after TAE/TEM does not compromise oncological results

safe at 6-8 weeks (adequate scar)Mayo data

Stage –matched cohort (n=52)

Completion radical = primary RR

Mainz data

Completion radical for pT2 = primary RR

Hahnloser D, DCR 2005 ; Borschitz T, DCR 2007

Conclusionnon-operative treatment not accepted paradigm yet(but appealing)

multimodal-defined cCR improves accuracy

patients should be enrolled in prospective registriesEuropean network for watchful waiting

Kfe.onk@slb.regionsyddanmark.dk

longer follow-up needed (>5 yrs.)