Yoo-Joung Ko

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?

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

Below the peritoneal reflection Different surgical approach

Total mesorectal excision (TME) Risk of local recurrence

Significant morbidity

False + T3 False + LN

Transrectal U/S

10% 30%

CT scan 20% 30%

MRI 20% 20%

Accurate pathologic staging Less likely to overtreat

Shorter delay to definitive therapy ie surgery

Potentially less surgical morbidity No complicated by prior XRT-chemo

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

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

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

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

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

Intergroup 0144, n=1917

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

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)

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

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

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%

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

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

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%

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%

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

Phil Quirke on behalf of the trial investigators and the UK NCRI colorectal cancer study group

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

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

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%

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%

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

1350 patients

Routine pre-op 5 x 5 Gy + TMEvs

TME + selective post-op chemoradiation for those with involvement of circumferential resection margin (CRM+)

1350

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

Incomplete TME

Complete TME

Excellent : 53%Average : 34%Bad: 13%

Excellent : 9%

Average : 12%

Bad: 19%

Oxaliplatin 50mg/m2 IV weekly X 5

In Whom?Which Regimen?For How Long?

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

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)

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

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

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

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

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

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)

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

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

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!!