1. RECTAL CANCER The (neo)adjuvant story
Mark Rother MD FRCPC
Medical Oncologist
Peel Regional Cancer Center
Credit Valley Hospital

2. Case
62 year old man (father of your life long best friend) has rectal bleeding
You get him in to see a GI specialist and a colonoscopy finds a non obstructing adenocarcinoma 6 cms from anal verge
CT Thorax/Abd/Pelvis – No mets

3. Your friend calls you for advice on the next step
Your friend calls you for advice on the next step? He has been reading up!
He thinks his Dad will need surgery, chemo and radiation based on his reading
He finds it all very confusing but knows you are an expert in GI oncology and will clarify it for him and his dad.

4. Questions? More Tests- MRI? EUS? Role of PET/CT?
Surgery- When? What type? Who should do it?
Radiation- Before/After surgery? Long protracted or intensive short type? With chemo or without?
Chemotherapy- What type? How long for? New drugs? Clinical trials? Must he get a PICC?

5. OVERVIEW Introduction Postoperative Chemoradiation
Preoperative Radiotherapy(no chemo)
Preoperative Chemoradiation
Preoperative vs Postoperative Chemoradiation
Optimizing Preoperative Chemoradiation
Postoperative chemotherapy after neoadjuvant CRT
Future Approaches

6. OVERVIEW Introduction Postoperative Chemoradiation
Preoperative Radiotherapy(no chemo)
Preoperative Chemoradiation
Preoperative vs Postoperative Chemoradiation
Optimizing Preoperative Chemoradiation
Postoperative chemotherapy after neoadjuvant CRT
Future Approaches

7. Rectal Cancer Estimated 6000 new cases per year in Canada
(30% of colorectal cancer)
Local and Systemic Relapse Risk
Prototype of a multimodality approach
Surgery
Radiation
Chemotherapy

8. Definition- Rectal Cancer
Discriminating between colon and rectal cancer is critical
Colon is 150 cm long but rectum is about the last cm
Anatomically, the upper boundary of the rectum is located at the rectosigmoid junction, slightly below the sacral promontory. On clinical grounds, the peritoneal reflection is the more important landmark

9. Definition - Rectal Cancer
In the post-operative setting the location of the tumour relative to the peritoneal reflection should be part of the surgical and pathological report
Identification of rectal tumours prior to surgery is generally obtained by measuring the distance between the inferior edge of the tumour and the anal verge(12-15cm)

10. Adjuvant therapy
Adjuvant therapy needs to address the local and systemic recurrence risk
Under-treatment : pelvic recurrences and complications
Over-treatment : therapy related complications - bowel, bladder and sexual dysfunction

11. Challenges in Adjuvant Therapy for Rectal Cancer
Data from randomized trials limited.
Debate on pre vs post op radiation and radiation dose and schedule is confusing
Chemotherapy concurrently with XRT-What and How?
Decisions on adjuvant chemo if received pre-op therapy.

12. OVERVIEW Introduction Postoperative Chemoradiation
Preoperative Radiotherapy(no chemo)
Preoperative Chemoradiation
Preoperative vs Postoperative Chemoradiation
Optimizing Preoperative Chemoradiation
Postoperative chemotherapy after neoadjuvant CRT
Future Approaches

13. OLDER APPROACH TO RECTAL CANCER (but still commonly done)
Surgical resection
Pathology assessment and risk estimation
Treatment based on TMN
Post operative Chemoradiation

14. 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:
GITSG
NCCTG-MAYO
JAMA 1990: 264:

15. 1990 NCI Consensus Statement
GITSG
(227) NEJM 1985
Surgery/5FU/mCCNU/RT
LR 11%
OS 56%
Surgery/5FU/mCCNU
LR 21%
OS 46%
Surgery/RT
LR 20%
OS 43%
Surgery
LR 24%
OS 32%
NCCTG
(204)
NEJM 1991
LR 14%
OS 58%
LR 25%
OS 48%

16. NCCTG Intergroup Study
660 patients with resected stage II/III rectal cancer
O’Connell NEJM 1994

17. NCCTG Intergroup Trial
2x2 study design:
PVI 5-FU vs bolus(with rads)
- Improved PFS (p=0.02)
- Improved OS (p=.01)
MeCCNU: no benefit
O’Connell NEJM 1994

18. Bolus 5FU-Leucovorin-Levamisole
Intergroup 0114 : Post-operative CT – CRT- CT
Bolus 5FU II
III
Bolus 5FU-Levamisole R
Bolus 5FU-Leucovorin
Bolus 5FU-Leucovorin-Levamisole
Tepper et al. JCO 2002 CP

19. Intergroup 0114 -OS by treatment arm
Tepper, J.E. et al. J Clin Oncol; 20:

20. II III R Intergroup 0144: Post operative CT – CRT - CT
b5FU – XRT+PVI5FU – b5FU II
III
PVI5FU – XRT+PVI5FU – PVI5FU R
b5FU/LV – XRT+b5FU/LV – b5FU/LV
Smalley, JCO2006

21. Intergroup 0144 - Overall survival and relapse-free survival
Smalley, S. R. et al. J Clin Oncol; 24:

22. Advantages of Postoperative Treatment
Accurate pathologic staging
Shorter delay to definitive surgery
Potentially less surgical morbidity?
Not complicated by prior XRT-chemo

23. Long-Term Effects of Postoperative Chemoradiation

24. OVERVIEW Introduction Postoperative Chemoradiation
Preoperative Radiotherapy(no chemo)
Preoperative Chemoradiation
Preoperative vs Postoperative Chemoradiation
Optimizing Preoperative Chemoradiation
Postoperative chemotherapy after neoadjuvant CRT
Future Approaches

25. Preop RT (25 Gy in 5 fractions)
Swedish Rectal Cancer Study
Preop RT (25 Gy in 5 fractions) R
LR 11%, 5yr OS 58%
Immediate surgery
LR 27%, 5yr OS 48%
NEJM 1997

26. Preop RT + TME (25 Gy in 5 fractions)
Dutch Colorectal Group (NEJM 2001)
Preop RT + TME (25 Gy in 5 fractions) R
LR 5.6%
TME alone
LR 10.9%
Kapiteijn NEJM 2001

27. MRC CR-07 (NCIC CO-16)
Lancet 2009; 373: 821–28

28. Lancet 2009; 373: 821–28

29. MRC CR07
Lancet 2009; 373: 821–28

30. MRC CR07

31. What about Short-course XRT?
2500 cGy in 5 fractions
Northern Europe approach
No concurrent chemo(5FU) radiosensitizer
Surgery within a 1-2 weeks
No downstaging(not for T4 or concern re CRM)
Concerns re long term bowel function
Studies ongoing with 6 week delay(?downstaging)-Stockholm lll

33. OVERVIEW Introduction Postoperative Chemoradiation
Preoperative Radiotherapy(no chemo)
Preoperative Chemoradiation
Preoperative vs Postoperative Chemoradiation
Optimizing Preoperative Chemoradiation
Postoperative chemotherapy after neoadjuvant CRT
Future Approaches

34. Preoperative Chemoradiotherapy
North American/Southern Europe approach
For patients with locally advanced disease
-T3/T4 or N+
More protracted RT course 5-6 weeks( cGy)
Concurrent 5FU based chemotherapy
Followed by Surgery weeks later
North American Standard

37. Bosset NEJM 2006

38. Bosset NEJM 2006

42. Polish Study Results 25/5 vs Chemoradiation Therapy pCR 1% vs. 19%
Similar SSS,DFS,OS
Similar late toxicity
Await similar design TROG study

43. TROG Study-ASCO 2010

44. OVERVIEW Introduction Postoperative Chemoradiation
Preoperative Radiotherapy(no chemo)
Preoperative Chemoradiation
Preoperative vs Postoperative Chemoradiation
Optimizing Preoperative Chemoradiation
Postoperative chemotherapy after neoadjuvant CRT
Future Approaches

45. INT- 0147
- terminated prematurely due to poor accrual
NSABP R-03
German Trial- CAO/ARO/AIO 94
- completed accrual

46. Volume 351: October 2004
Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group

47. Results -Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal Cancer Study Group
421 receive preoperative and 402 receive postoperative chemoradiotherapy.
The overall five-year survival rates were 76 percent and 74 percent (P=0.80).
The five-year incidence of local relapse 6 percent for preoperative and 13 percent in the postoperative group (P=0.006).
Grade 3 or 4 acute toxicity occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001)
Sauer NEJM 2004

48. Sauer NEJM 2004
Sauer NEJM 2004

49. Sauer NEJM 2004

50. Sphincter Preserving Surgery
ITT Analysis
Postoper. RCT Preoper. RCT
n= n = 405
17/85 (20%) /109 (39%)
85-17= = 66
Pre-randomization:
“APR Necessary“
Sphincter
preserved
p = 0.004
APR actually done

51. 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

52. CAVEAT
18% of tumours in the post operative group were overstaged clinically (i.e. Stage 1 on pathology)
Mandates excellent preoperative radiologic assessment

53. Preoperative Rectal Staging
Accurate preoperative local tumor staging is critical in directing patient management
All modalities remain poor in assessment of regional lymph node involvement
CT still the workhorse for distant metastatic disease, complications/sequelae and surveillance

54. OVERVIEW Introduction Postoperative Chemoradiation
Preoperative Radiotherapy(no chemo)
Preoperative Chemoradiation
Preoperative vs Postoperative Chemoradiation
Optimizing Preoperative Chemoradiation
Postoperative chemotherapy after neoadjuvant CRT
Future Approaches

55. 5FU as a radiosensitizer
Improves local control, pCR (FFCD,EORTC)
Potentially improves control at distant sites (treats micro metastasis earlier)
PVI is the optimal schedule

56. Capecitabine as a Radiosensitizer?
Mimics infusional 5FU
Convenient versus PVI
Intratumoral thymidine phosphorylase activity upregulated with XRT

57. Oral vs Infusional 5FU N PCR (%) SSS (%) 94 9% 25% 36 53 24% 59% 95N
PCR (%)
SSS (%)
Phase2, UFT 400mg/m2/d X 5/7 – S – 5FU/LVX4 (1) 94 9%
25%
Phase1 – RP2D Capecitabine 825mg/m2 BID X 7/7 (2) 36 --
Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (3) 53
24%
59%
Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (4) 95
12%
74%
Matched-Pair Analysis (PVI vs Capecitabine) (5)
89/89
12%/21%
70%/78%
Similar OS N
PCR (%)
SSS (%)
Phase2, UFT 400mg/m2/d X 5/7 – S – 5FU/LVX4 (1) 94 9%
25%
Phase1 – RP2D Capecitabine 825mg/m2 BID X 7/7 (2) 36 --
Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (3) 53
24%
59%
Phase 2, Capecitabine 825mg/m2 BID X 7/7 – S – C X 4/12 (4) 95
12%
74%
Matched-Pair Analysis (PVI vs Capecitabine)
89/89
12%/21%
70%/78%
1 – Fernandez, JCO – Dunst, JCO 2002
3 – DePaoli, Ann Oncol – Kim, IJROBP 2005
5 – Das, IJROBP, 2006

58. Capecitabine versus 5-fluorouracil-based
(neo-)adjuvant chemo-radiotherapy
for locally advanced rectal cancer:
Long term results of a randomized phase III trial
R. Hofheinz, F. Wenz, S. Post, on behalf of the German MARGIT study
Dear chairmen, dear ASCO members and guest, ladies and gentlemen,
first of all I would like to thank to the ASCO scientific programme committe for selecting this abstract for preentation and to give me the opportunity to present the data on behalf of my colleagues
Moreover, I would also like to thank all patients and their relatives and of course all physicians participating in this study.
The present trial represent an investigator initiaited randomized trial comparing capecitabine and 5-FU in the perioperative treatment of locally advanced rectal cancer.

59. Study Design Mar 2002-July2005 Post-Op Treatment Post July 2005
After Publication
of Sauer Trial
Neoadjuvant
Treatment
Arms Added

60. Overall survival (OS) Primary endpoint (Median Follow-up 52 mon.)

61. Disease free survival (DFS) Secondary endpoint (Median Follow-up 52 mon.)

62. NSABP-R04 Oxaliplatin 1200 pts
No Oxaliplatin
1200 pts
5FU
Capecitabine
***Capecitabine is 825 mg /m2 bid for 5/7(Rad days)
Roh et al ASCO 2011

63. NSABP-R04
Roh et al ASCO 2011

64. NSABP-R04
Roh et al ASCO 2011

65. 5FU-Oxaliplatin-XRT
Over 15 phase I/II trials have demonstrated pCR rates ranging from 20-40% (compared to 10-20% expected with XRT+5-FU)
Increased likelihood for sphincter preservation?
More efficacious systemic therapy for micrometastases given preoperatively?

66. NSABP-R04
Roh et al ASCO 2011

67. NSABP-R04 Sphincter Saving Surgery by Treatment Oxaliplatin vs None
Pathologic Complete Response by Treatment Oxaliplatin vs None
Roh et al ASCO 2011

68. STAR TRIAL
Aschele C et al. J Clin Oncol July 2011

69. STAR TRIAL RESULTS 5-FU CRT 5-FU/Oxal CRT p-value Path CR 16% 0.94
Gr 3-4 toxicity
Any
Diarrhea 8% 4%
24%
15%
<0.0001
Grade 2-3 neurosensory
0.5%
36%
Aschele C et al. J Clin Oncol July 2011

70. ACCORD 12/0405-Prodige 2
Eligibility
T3-4, N0-2, M0 resectable (or T2 distal anterior) rectal cancer, DRE accessible R
CAPE/RT45
RT 45 Gy x 5 wks
CAPE 800 mg/m2 BID/day*
CAPOX/RT50
RT 50 Gy x 5 wks
CAPE 800 mg/m2 BID/day*
OXA 50 mg/m2 weekly
(6 weeks)
*Except weekend
Total Mesorectal Excision (TME)
Adjuvant chemotherapy (Center discretion)
Gerard JP et al. J Clin Oncol 2010;28(10):

71. ACCORD 12 TRIAL RESULTS
CAP/RT
CAPOX/RT
p-value
Path CR
14%
19%
0.11
Gr 3-4 toxicity
Any
Diarrhea
Neuropathy
11% 3%
0.4%
25%
13% 5%
<0.001
<0.002
Standard of care remains 5-FU based neoadjuvant CRT without oxaliplatin.
Gerard JP et al. J Clin Oncol 2010;28(10):

72. OVERVIEW Introduction Postoperative Chemoradiation
Preoperative Radiotherapy(no chemo)
Preoperative Chemoradiation
Preoperative vs Postoperative Chemoradiation
Optimizing Preoperative Chemoradiation
Postoperative chemotherapy after neoadjuvant CRT
Future Approaches

73. Decline in the rates of local failure:1980-2010 The war we are winning35 30 25 20 15 10 5
Local failure (%)
Local failure: the war we are winning
· SX only: 30% norvegese
25% NSABP R-01
24% GITSG 1*
· SX + RT: 25% Mayo-NCCTG*
20% GITSG 1*
16% NSABP R-01
· SX + CMT: 16% GITSG 2*
13% Mayo-NCCTG*
12% norvegese
11% GITSG 1*
11% INT y (media)
8% NSABP R02*
7% INT-PVI (media)
· TME +RT : 3% Dutch
sx only sx  RT sx  CTRT CTRT  TME

74. Deline in the rates of distant failures: 1980-2010 The war we are losing40 35 30 25 20 15 10 5
Distant metastases (%)
Local failure: the war we are winning
· SX only: 30% norvegese
25% NSABP R-01
24% GITSG 1*
· SX + RT: 25% Mayo-NCCTG*
20% GITSG 1*
16% NSABP R-01
· SX + CMT: 16% GITSG 2*
13% Mayo-NCCTG*
12% norvegese
11% GITSG 1*
11% INT y (media)
8% NSABP R02*
7% INT-PVI (media)
· TME +RT : 3% Dutch
sx only sx  RT sx  CTRT CTRT  TME

75. (NCCTG 794751, 864751; NSABP R01, R02; INT 0114) n=3791
Postoperative chemotherapy in Rectal Cancer
(no preoperative treatment in these studies)
(NCCTG , ; NSABP R01, R02; INT 0114) n=3791 CT
No CT
Gunderson, L. L. et al. J Clin Oncol; 22:

76. Postoperative chemotherapy in Rectal Cancer
QUASAR STUDY-Rectal Cohort(29%) n=948
Recurrence free survival
Overall survival
Lancet 2007 Lancet 2007; 370: 2020–29; 370: 2020–29

77. Postoperative chemotherapy in Rectal Cancer ECOG 3201
5FU/LV
Stage II/II
Rectal Cancer
Preop or Postop CRT
(MD Choice) R
FOLFOX4
FOLFIRI
Closed at 225 of planned 3150

78. Bosset NEJM 2006

79. Bosset NEJM 2006

80. Who benefits from post operative 5FU?
(ypT downsized)
Collette, L. et al. J Clin Oncol; 25:

81. Postoperative chemotherapy after neoadjuvant CRT
5FU/FA:
-Only trend in EORTC study(negative)-Only level 1 study to date
-Standard in postoperative CRT era-QUASAR,INT 0114/0144
Xeloda:
-Only extrapolation from stage 3 colon cancer(X-ACT)
FOLFOX:
-Only extrapolation from stage 3 colon cancer(MOSAIC,CO7)

82. Postoperative chemotherapy after neoadjuvant CRT
All patients should get some chemo regardless of ypT ypN statusplan set preoperatively
Duration should be 4 months
Choice of Xeloda vs FOLFOX individualized
If no downstaging- FOLFOX?
If short-course preop-XRT – 6 months

83. STUDIES OF CHEMOTHERAPY IN RECTAL CANCER
Pre-op:
STAR( 5FU +/- OXALIPLATIN)-Published JCO ACCORD(XELODA +/- OXALIPLATIN)- Published JCO NASBP R-04( 5FU vs. XELODA +/- OXALIPLATIN)-ASCO 2011
Post-op:
SCRIPT (XELODA vs. Nil)-Closed for accrual issues
CHRONICLE (XELOX vs. Nil)- Closed for accrual issues
E5204 (FOLFOX +/-AVASTIN)- Closed for accrual issues
Pre and Post-op:
CAO/ARO/AIO 04(5FU+/-Oxaliplatin---PRE/POST)- report PETACC-6(XELODA +/- OXALIPATIN---PRE/POST)-ongoing

84. SCRIPT STUDY Operable Rectal Cancer-Clinical Stage2/3 ↓
Preop CRT/5 day rads
TME surgery
Randomization
Observation Capecitabine
CLOSED DUE TO POOR ACCRUAL

85. CHRONICLE STUDY
CLOSED DUE TO POOR ACCRUAL

86. ECOG 5204 Phase III Trial (NCIC CRC.4)
mFOLFOX6 X 12 R
Stage II/III
mFOLFOX6 + Bev X 12
Accrual: 2100 planned- CLOSED DUE TO ACCRUAL -2009

87. CAO/ARO/AIO 04
Rodel et al ASCO 2011

88. CAO/ARO/AIO 04
Rodel et al ASCO 2011

89. CAO/ARO/AIO 04
Rodel et al ASCO 2011

90. CAO/ARO/AIO 04
Conclusion
Rodel et al ASCO 2011

91. PETACC 6
ONGOING

92. OVERVIEW Introduction Postoperative Chemoradiation
Preoperative Radiotherapy(no chemo)
Preoperative Chemoradiation
Preoperative vs Postoperative Chemoradiation
Optimizing Preoperative Chemoradiation
Post operative adjuvant chemotherapy
Future Approaches

93. Newer approaches-Phase 2

94. Newer approaches-Phase 2

95. Newer approaches-Phase 2
EXPERT trial

96. Newer approaches-Phase 2

97. Newer approaches-Phase 2

98. Newer approaches-Phase 2

99. Newer approaches-Phase 2

100. Newer approaches-Phase 2
Patients with
progressive or
stable disease 
XRT + 5-FU
Newly diagnosed clinical stage II or III rectal adenocarinoma
FOLFOX + Bev
FOLFOX + Bev x 4
 FOLFOX x 2
Patients with
clinical regression
 Surgery*
*Post-operative treatment at
discretion of physician.
FOLFOX x 6 recommended; no
post-operative Bev provided.
Schrag D et al. Proc ASCO 2010;Abstract 3511.

101. Newer approaches-Phase 2
31 patients with Stage II/III (no T4) rectal
27/27 patients had regression and proceeded to surgery with no XRT
27 had R0 resection and 7/27 (26%) pCR
One pt with 14/14 nodes offered post-op XRT
Schrag D et al. Proc ASCO 2010;Abstract 3511.

102. CALGB Phase II/III “PROSPECT” study

103. Newer approaches-Phase 2

104. SUMMARY APPROACH TO RECTAL CANCER-2011
Accurate preoperative imaging -MRI Staging
Multidisciplinary Tumour Board discussion
Use of preoperative radiation with or without chemotherapy
Surgical concept of TME resections
Pathologists “auditing” the surgical procedure
-TME quality, CRM, nodal recovery
Postoperative chemotherapy

105. Questions