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Organ sparing-strategy in rectal cancer Importance – How can we progress ?. A.D’Hoore MD PhD , A. Wolthuis MD, F. Penninckx MD PhD K. Haustermans MD PhD*, E. Van Cutsem MD PhD** V. Vandecaveye MD PhD*** Department of Abdominal Surgery, Radiation Oncology*, GI Oncology** and Radiology*** - PowerPoint PPT Presentation
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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
longer follow-up needed (>5 yrs.)