1. Rectal Cancer MOTP Half Day September 9, 2008
Yoo-Joung Ko

2. Outline Rectal Anatomy Evidence Importance of Quality of TME
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?

3. Rectal Anatomy Pelvic size/structures: M vs. F Portion of Rectum
Left upper valve of Houston
cm from
anal verge
Right middle valve of Houston
upper 1/3
middle 1/3
lower 1/3 15
Peritoneum 10
Ampulla of
Rectum
Left lower valve
of Houston 6
20. Rectum: Anatomy
The rectum is approximately 15 cm long and can be divided into the upper, middle, and lower thirds. Rectal cancer is localized by reference to the anal verge, dentate line, or anorectal ring.
Pelvic size/structures: M vs. F
Anal verge
Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1197.

4. Rectal Cancer: Unique Aspects
Below the peritoneal reflection
Different surgical approach
Total mesorectal excision (TME)
Risk of local recurrence
Significant morbidity

5. Rectal Cancer Staging False + T3 False + LN Transrectal U/S 10% 30%
CT scan
20%
MRI

6. Post Op Combined Modality

7. Advantages of Postoperative Treatment
Accurate pathologic staging
Less likely to overtreat
Shorter delay to definitive therapy ie surgery
Potentially less surgical morbidity
No complicated by prior XRT-chemo

8. 1990 NCI Consensus Statement
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:

9. NCCTG Intergroup Trial (postop trial)
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

10. Bolus 5FU-Leucovorin-Levamisole
Tepper, JCO 1997
Intergroup 0114 CT – CRT - CT
Bolus 5FU II
III
Bolus 5FU-Levamisole R
Bolus 5FU-Leucovorin
Bolus 5FU-Leucovorin-Levamisole CP

11. Intergroup 0114 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

12. PVI5FU – XRT+PVI5FU – PVI5FU b5FU/LV/LEV – XRT+5FU/LV – b5FU/LV/LEV
Intergroup 0144
b5FU – XRT+PVI5FU – b5FU II
III
PVI5FU – XRT+PVI5FU – PVI5FU R
b5FU/LV/LEV – XRT+5FU/LV – b5FU/LV/LEV
Smalley, JCO2006

13. Intergroup 0144, n=1917
Overall survival in the three arms is shown here with arm A (PVI only during XRT) in white; arm B (consistent PVI throughout therapy) in orange; and arm C biochemically modulated bolus 5-FU alone in yellow.
Stratified cox model analysis of these 3 arms yielded a p value of 0.14
Less hematologic toxicity with bolus FU

14. Preoperative Radiotherapy

15. Preoperative Therapy Lack of surgical staging
Potential overtreatment minimized by better imaging
XRT better tolerated (tissues better oxygenated)
Sphincter preservation
Less small bowel irradiation
?early irradication of micrometastatic disease

16. Preop RT (25 Gy in 5 fractions)
Swedish Rectal Cancer Study
Decrease LR and improves OS
Preop RT (25 Gy in 5 fractions) R
LR 11%, 5yr OS 58%
Immediate surgery
TME not uniform
High local recurrence rates in both arms
No chemotherapy
hypofractionation
LR 27%, 5yr OS 48%
(NEJM 1997)

17. TME + Preop RT (25 Gy in 5 fractions)
Dutch Colorectal Group (NEJM 2001)
No OS benefit at 2 yrs
TME + Preop RT (25 Gy in 5 fractions) R
LR 2.4%*, 2yr OS 82%
TME alone
Evaluate preop therapy in addition to TME
No survival benefit at 2 years
No chemotherapy
Hypofractionation
LR 8.2%, 2yr OS 82%
*62% rate of fecal incontinence with XRT

18. Preoperative vs Postoperative XRT

19. German Rectal Cancer Study Group,
Adjuv. vs. neoadjuv. CRT (CAO/ARO/AIO-94)
5-FU FU FU FU FU FU
5 x 1000 mg/m2 5 x 1000 mg/m mg/m2/d
120h-infusion h-infusion i.v.-bolus S
Arm I:
RT: Gy Boost
5-FU FU FU FU
500 mg/m2/d
I.v.bolus
5-FU FU
5 x 1000 mg/m x 1000 mg/m2
120h-infusion h-infusion S
Arm II:
2 prior US studies comparing Preop and Postop closed due to poor accruel
RT: 50.4 Gy
Weeks
Sauer NEJM 2004

20. Intent-to-treat Analysis (Med. Follow-up: 40 mts)
Overall Survival
Intent-to-treat Analysis (Med. Follow-up: 40 mts)
Overall Survival
1.0
Postop CRT .9
74%
Overall Survival .8
Preop CRT
74% .7
Primary endpoint .6 10 20 30 40 50 60
Months

21. Chronic Toxicity (Grade 3/4) Analysis per protocol
Postop. RCT
14.8 %
11.8 %
3.4 %
22.7 %
Preop. RCT
9.5 %
4.0 %
2.2 %
9.6 %
Gastrointestinal
Anastomosis
Bladder
All Toxicities
n.s.
0.006
0.04

22. Sphincter Preserving Surgery
ITT Analysis
Postoper. RCT Preoper. RCT
n= n = 405
17/85 (20%) /109 (39%)
Pre-randomiz:
“APR
Necessary“
More distal tumors in the preop arm
Sphincter
preserved
p = 0.004

23. 12% 6% Cumulative Incidence of Local Relapses
Intent-to-treat Analysis (Med. Follow-up: 40 mts) 60 50 40 30 20 10
.14
.12
.10
.08
.06
.04
.02
0.00
Months
12%
Postop CRT
Locoregional Recurrences 6%
p = 0.006
Preop CRT

24. Cumulative Incidence of Metastases
Intent-to-treat Analysis (Med. Follow-up: 40 mts) 60 50 40 30 20 10 .4 .3 .2 .1
0.0
Months
Distant Metastases
32%
Postop CRT
32%
Preop CRT

25. German Rectal Study Conclusions
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
18% in postop arm were overstage (ie initially T3/T4 but really T1/2)

26. Local recurrence after rectal cancer resection is strongly related to the plane of surgical (PoS) dissection and is further reduced by pre-operative short course radiotherapy Preliminary results of the MRC CR07/NCIC C016 randomised trial
Phil Quirke
on behalf of the trial investigators
and the UK NCRI colorectal cancer study group

27. Trial Design POST PRE Adjuvant chemotherapy given as per local policy
Clinically operable adenocarcinoma of the rectum
<15cm from anal verge; no metastases
Randomise
POST
PRE
Pre-operative RT
25Gy / 5F
Surgery
Pathology (Pos)
Surgery
CRM-ve
CRM+ve
Pathology (PoS)
CRM-ve
CRM+ve
No RT
Post-op CRT
45Gy / 25F
+ concurrent
5FU
Adjuvant chemotherapy given as per local policy

28. CRO7/NCIC CO.16 Equivalence study Pre-op (n=674)
Selected post-op (n=676)
p value
Surgery: Anterior resection
APR
60%
31%
63% NS
Anastomotic leak 8% 7%
CRM positivity
10%
12%
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

29. 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
% 76%
CR07 25 Gy / 5 tx 5% 72%
To place these results in context, compared to a few recently-reported high-profile analyses, the preoperative CR07 patients fared as well as those in the German trial administering more prolonged radiation and somewhat better than those evaluated in the large meta-analysis and in the Swedish study that also included 25 Gy short-course radiation.

30. Pre-op vs Post-op (cont.)
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 % %
Intergroup % %
CR07 (45 Gy) % 61.7%
The postoperative CR07 patients, however, did not fare as well – particularly compared to the two US Intergroup postoperative chemoradiation adjuvant trials, nor to the postoperative radiation group in the German trial. Of note, all three of these previously-reported trials administered higher dose radiation.

31. CO.16 - Summary 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

32. High efficacy of short-course schedule also has been confirmed by the MRC CR07 randomized trial (ASCO Meeting 2006 )
1350 patients Routine pre-op 5 x 5 Gy + TME vs TME + selective post-op chemoradiation for those with involvement of circumferential resection margin (CRM+)

33. The MRC C-07 study
1350

34. MRC CR07 trial: 5-year results
Routine pre-op Selective post-op 5 x 5 Gy chemoradiation Local recurrence 5% 17% p<.001 Disease-free surv. 75% 67% p=.03 Overall surv. 72% 62% p=.07

35. Prognosis QOL of surgery
Complete TME
Incomplete TME

36. MCR- C07 study: Quality of TME Surgery
Excellent : 53%
Average : 34%
Bad: 13%

37. MCR- C07 study: Quality of TME Surgery and CRM+
Excellent : 9%
Average : 12%
Bad: 19%

38. Controversies

39. Optimizing Preoperative Chemoradiation

40. Can we replace PVI-5FU with Capecitabine With RT
Can we replace PVI-5FU with Capecitabine With RT? What about Oxalilatin with RT?

41. NSABP R-04
Oxaliplatin 50mg/m2 IV weekly X 5

42. Postoperative/Post CRT – Adjuvant Chemotherapy
In Whom?
Which Regimen?
For How Long?
Postoperative/Post CRT – Adjuvant Chemotherapy

43. Unanswered Questions Remain
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

44. Which Regimen?

45. PETACC-6: T3,4 or N+ Rectal Cancer
R0-resectability certain
XRT 5 x 5 Gy
XRT 45 Gy +/- 5.4 Gy Boost with Cape or FU
R0-resectability uncertain XRT 45 Gy +/- 5.4 Gy Boost with Cape or FU T M E
Cape 6 mos.
5-FU bolus
(NCI consensus/ previous German trial)
XRT 45 Gy +/- 5.4 Gy Boost with XELOX
XELOX
4 – (6) mos.
German protocol from previous trial (AIO/ARO/CAO-94)

46. ECOG 5204 Phase III Trial (NCIC CRC.4)
mFOLFOX6 X 12
Stage II/II
Preop CRT (Cape, FU)
-NSABP R04
IF preop oxali:
9 cycles mFOLFOX6 +
3 cycles 5FU/LV R
mFOLFOX6 + Bev X 12
Accrual: 2100 planned

47. Is there a current standard?
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

48. Conclusions Unique aspects of rectal cancers
Preop Chemoradiation reduces local recurrences and may improve OS
Longer radiation with infusional FU standard
Optimal preop staging critical
Surgical TME techinque important
Postop chemotherapy important
Optimal chemotherapy and duration of treatment not yet defined

49. In Whom?

50. Who is high risk?
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

51. Prognostic factors – Pretreatment cT/cN?
cT2 (n=16)
cT3
(n=268)
cT4
(n=24)
Disease-free Survival
1.0 .8 .6 .4 .2 20 40 60 80
100
Months
cN+ (n=213)
cN0 (n=154)
p=0.92
p=0.34

52. Prognostic factors – ypT/ypN
Disease-free survival after R0-resection (n=344)
1.0
ypT1
1.0
ypT0
ypNO .8 .8
ypT2
ypN1
ypT3 .6 .6
Disease-free Survival
ypT4 .4 .4
ypN2 .2 .2
p=0.001
p<0.0001 20 40 60 80
100 20 40 60 80
100
Months
Months

53. Moderate/Good Regression
No/Minimal
Regression
TRG 0+1
(n=27)
Moderate/Good Regression
TRG 2+3
(n=77)
ypT3 ypN0
M0 R0
Submucosa T1
Muscularis propria T2
Subserosa T3
Adjacent organs T4
TRG 4 : No Viable Primary Tumour

55. Prognostic factors – Multivariate analysis
p-Value Odds ratio
Disease-Free Survival:
ypT category
ypN category <
Metastases-Free Survival:
ypT category
ypN category <
Local Relapse-Free Survival
ypN category <

56. Summary and Conclusion
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!!