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Yoo-Joung Ko
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Rectal Anatomy Unique aspects of a rectal primary
Evidence Post Op Combined Modality Pre Op Pre Op vs Post Op
Importance of Quality of TME Controversies
Colon CA What regimen do? How long should we treat? Who should we treat?
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Left upper valve of HoustonLeft upper valve of Houston
Right middle valve of HoustonRight middle valve of Houston
PeritoneumPeritoneum
Left lower valve Left lower valve of Houstonof Houston
Anal vergeAnal verge
AmpullaAmpullaof of RectumRectum
66
1010
1515upper 1/3upper 1/3
middle 1/3middle 1/3
lower 1/3lower 1/3
PortionPortionofofRectumRectum
cm fromcm fromanal vergeanal verge
Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1197.
Pelvic size/structures: M vs. F
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Below the peritoneal reflection Different surgical approach
Total mesorectal excision (TME) Risk of local recurrence
Significant morbidity
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False + T3 False + LN
Transrectal U/S
10% 30%
CT scan 20% 30%
MRI 20% 20%
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Accurate pathologic staging Less likely to overtreat
Shorter delay to definitive therapy ie surgery
Potentially less surgical morbidity No complicated by prior XRT-chemo
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Combined postoperative chemotherapy and radiation improves local control and survival in patients with stage II and III rectal cancer and is recommended
JAMA 1990: 264:1444-1450
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2x2 study design:–PVI 5-FU during XRT better
•significant decrease in relapse (47% to 37%, p=0.01)
•reduction in distant metastases (40% to 31%, p=0.03)
•no difference in local failure rate
–MeCCNU: no benefit NEJM 1994
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CP1050909-25
RR
Intergroup 0114CT – CRT - CT
Bolus 5FUBolus 5FU
IIIIIIIIII
Bolus 5FU-LevamisoleBolus 5FU-Levamisole
Bolus 5FU-LeucovorinBolus 5FU-Leucovorin
Bolus 5FU-Leucovorin-LevamisoleBolus 5FU-Leucovorin-Levamisole
Tepper, JCO 1997
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1696 patients with resected stage II/III rectal cancer
Similar toxicity, similar efficacy – no difference in DFS or OS
Local Recurrence rate 14-18%5year OS – 61-65%
Tepper, JCO 1997
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RR
Intergroup 0144
b5FU – XRT+PVI5FU – b5FUb5FU – XRT+PVI5FU – b5FU
IIIIIIIIII
PVI5FU – XRT+PVI5FU – PVI5FUPVI5FU – XRT+PVI5FU – PVI5FU
b5FU/LV/LEV – XRT+5FU/LV – b5FU/LV/LEVb5FU/LV/LEV – XRT+5FU/LV – b5FU/LV/LEV
Smalley, JCO2006
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Intergroup 0144, n=1917
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Lack of surgical staging Potential overtreatment minimized by better imaging
XRT better tolerated (tissues better oxygenated)
Sphincter preservationLess small bowel irradiation?early irradication of micrometastatic disease
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Swedish Rectal Cancer StudySwedish Rectal Cancer StudyDecrease LR and improves OSDecrease LR and improves OS
Swedish Rectal Cancer StudySwedish Rectal Cancer StudyDecrease LR and improves OSDecrease LR and improves OS
Preop RTPreop RT(25 Gy in 5 fractions)(25 Gy in 5 fractions)
Immediate surgeryImmediate surgery
RRLR 11%, 5yr OS 58%
LR 27%, 5yr OS 48%
(NEJM 1997)(NEJM 1997)
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TME + Preop RTTME + Preop RT(25 Gy in 5 fractions)(25 Gy in 5 fractions)
TME aloneTME alone
RRLR 2.4%*, 2yr OS 82%
LR 8.2%, 2yr OS 82%
Dutch Colorectal Group (NEJM 2001)No OS benefit at 2 yrs
*62% rate of fecal incontinence with XRT
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0 2 4 6 8 10 12 14 16 18 20 22 Weeks
German Rectal Cancer Study Group, Adjuv. vs. neoadjuv. CRT (CAO/ARO/AIO-94)
S
5-FU 5-FU5 x 1000 mg/m2 5 x 1000 mg/m2
120h-infusion 120h-infusion
RT: 50.4 Gy
Arm II:
5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5 x 1000 mg/m2 5 x 1000 mg/m2 500 mg/m2/d120h-infusion 120h-infusion i.v.-bolus
RT: 50.4 + 5.4 Gy Boost
Arm I:
5-FU 5-FU 5-FU 5-FU 500 mg/m2/d I.v.bolus
S
Sauer NEJM 2004
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Overall SurvivalIntent-to-treat Analysis (Med. Follow-up: 40 mts)
Overall Survival
6050403020100
1.0
.9
.8
.7
.6
Months
Ove
rall
Su
rviv
al
Preop CRT
Postop CRT
74%
74%
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Gastrointestinal
Anastomosis
Bladder
All Toxicities
Postop. RCT
14.8 %
11.8 %
3.4 %
22.7 %
Preop. RCT
9.5 %
4.0 %
2.2 %
9.6 %
n.s.
0.006
n.s.
0.04
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Sphincter Preserving SurgeryITT Analysis
Pre-randomiz:“APR
Necessary“
Postoper. RCT Preoper. RCT
n= 394 n = 405
85 109
17/85 (20%) 43/109 (39%)Sphincter
preservedp = 0.004
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Cumulative Incidence of Local RelapsesIntent-to-treat Analysis (Med. Follow-up: 40 mts)
6050403020100
.14
.12
.10
.08
.06
.04
.02
0.00
Months
Lo
core
gio
nal
Rec
urr
ence
s
p = 0.006
Postop CRT
Preop CRT
12%
6%
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Cumulative Incidence of MetastasesIntent-to-treat Analysis (Med. Follow-up: 40 mts)
6050403020100
.4
.3
.2
.1
0.0
Months
Dis
tan
t M
etas
tase
s
Postop CRT
Preop CRT
32%
32%
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Preop CRT significantly improves local control
Preop CRT improves sphincter preservation in low-lying tumours
Preop CRT reduced acute and chronic toxicity
Preop CRT should be the standard adjuvant treatment in cT3/4 or cN+ rectal cancer
NO effect on overall survival
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Phil Quirke on behalf of the trial investigators and the UK NCRI colorectal cancer study group
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Randomise
Clinically operable adenocarcinoma of the rectum <15cm from anal verge; no metastases
Adjuvant chemotherapy given as per local policy
PRE POST
Pre-operative RT25Gy / 5F
Surgery
Surgery
Pathology (Pos)
CRM-ve CRM+ve
Post-op CRT45Gy / 25F
+ concurrent5FU
No RT
Pathology (PoS)
CRM-ve CRM+ve
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Equivalence study Pre-op (n=674)
Selected post-op (n=676)
p value
Surgery: Anterior resection
APR
60%
31%
63%
31%
NS
Anastomotic leak 8% 7% NS
CRM positivity 10% 12% NS
T/N staging More T3
5y Local recurrence (1o endpt) 5% 17% HR=2.47
p<0.0001
Distant metastases N=98 N=106
3y DFS 80% 75% 0.03
3y OS (early for this endpoint) 81% 79% 0.07
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Local Recurrence: Pre-op vs Post-op
Pre-op Surgery S + RT Survival
Meta-analysis 22% 12.5% S + RT 45%S 42%
Swedish Trial (25 Gy, 5 tx) 27% 12% S + RT 58%S 48%
Dutch (TME) Trial 8.2% 2.4%
German 50.4 Gy - 54 6% 76%
CR07 25 Gy / 5 tx 5% 72%
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Local Recurrence: Pre-op vs Post-op (cont.)
Post-op Surgery S + RT Survival
German Trial (50.4—54.0 Gy, 5 tx) 13% 74%
Intergroup 0114 50.4 -- 54 9-13% 53-67%
Intergroup 0144 50.4 -- 54 4.6-8% 67-72%
CR07 (45 Gy) 17% 61.7%
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Local recurrence rate is significantly reduced with
pre-op RT compared to post-op RT Results after post-op chemo/RT poor
comared to other trials and are especially poor for Stage III and CRM-positive patients
Study included patients not usually considered for
RT* Stage I (315/1211 pts)
Many patients did not receive optimal TME (523/1119) pts
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1350 patients
Routine pre-op 5 x 5 Gy + TMEvs
TME + selective post-op chemoradiation for those with involvement of circumferential resection margin (CRM+)
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1350
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Routine pre-op Selective post-op 5 x 5 Gy chemoradiationLocal recurrence 5% 17% p<.001Disease-free surv. 75% 67% p=.03Overall surv. 72% 62% p=.07
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Incomplete TME
Complete TME
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Excellent : 53%Average : 34%Bad: 13%
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Excellent : 9%
Average : 12%
Bad: 19%
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Oxaliplatin 50mg/m2 IV weekly X 5
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In Whom?Which Regimen?For How Long?
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In Whom? Clinical stage versus Pathologic stage
▪ Downstaged to pathologic CR (ypCR)…
Which regimen? 5FU/LV versus Capecitabine versus FOLFOX
For How Long? 4 months versus 6 months
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R0-resectability certainXRT 5 x 5 GyXRT 45 Gy +/- 5.4 Gy Boost with Cape or FU
R0-resectability uncertainXRT 45 Gy +/- 5.4 Gy Boost
with Cape or FU
XRT 45 Gy +/- 5.4 Gy Boost with XELOX
T
M
E
Cape 6 mos. 5-FU bolus (NCI consensus/ previous German trial)
XELOX 4 – (6) mos.
PETACC-6: T3,4 or N+ Rectal Cancer
German protocol from previous trial (AIO/ARO/CAO-94)
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Stage II/II
Preop CRT (Cape, FU)-NSABP R04
R
mFOLFOX6 X 12
mFOLFOX6 + Bev X 12
Accrual: 2100 planned
IF preop oxali:9 cycles mFOLFOX6 + 3 cycles 5FU/LV
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Concurrent Preop long-course XRT Continuous infusion 5FU* Capecitabine being studied
Adjuvant Chemotherapy Consider in all pts who receive CRT
▪ ? Group who doesn’t need post op therapy - ? Path CR 5FU/LV X 4 cycles is a standard Capecitabine may be an option FOLFOX is a reasonable option
▪ particularly in higher risk▪ How do we define risk?
Minimum duration of 4 months
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Unique aspects of rectal cancersPreop Chemoradiation reduces local recurrences and may improve OS
Longer radiation with infusional FU standard
Optimal preop staging criticalSurgical TME techinque importantPostop chemotherapy important
Optimal chemotherapy and duration of treatment not yet defined
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Prognostic data from Sauer trial may help (Rodel, JCO 2005) in absence of definitive data to define risk in patients having had pre-op chemo rads
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Prognostic factors – Pretreatment cT/cN?
cT2 (n=16)
cT3(n=268)
cT4(n=24)
Dis
ease
-fre
e S
urv
ival
1.0
.8
.6
.4
.2
020 40 60 80 1000
Months
1.0
.8
.6
.4
.2
020 40 60 80 1000
Months
cN+ (n=213)
cN0 (n=154)
p=0.92 p=0.34
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Prognostic factors – ypT/ypN
ypT4
ypT3
ypT2
ypT1ypT0
Dis
ease
-fre
e S
urv
ival
1.0
.8
.6
.4
.2
020 40 60 800
Months100
ypNO
ypN2
ypN1
1.0
.8
.6
.4
.2
020 40 60 80 1000
Months
p=0.001 p<0.0001
Disease-free survival after R0-resection (n=344)
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Adjacent organs T4
Submucosa T1
Muscularis propria T2
Subserosa T3
No/MinimalRegression
TRG 0+1(n=27)
Moderate/Good Regression
TRG 2+3(n=77)
ypT3 ypN0 M0 R0
TRG 4 : No Viable Primary Tumour
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Prognostic factors – Multivariate analysis
p-Value Odds ratio
Disease-Free Survival:ypT category 0.016 1.48 ypN category <.0001 2.68
Metastases-Free Survival:ypT category 0.014 1.49ypN category <.0001 2.59
Local Relapse-Free SurvivalypN category <0.001 3.86
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cT/cN: no significant prognostic impact
– room for improvement! ypT/ypN: strongest prognostic factors – treatment stratification?
TRG: discrimination of pts. with identical ypTNM?
Need validation!!