1. Adjuvant Chemotherapy for Colorectal Cancer
Ronald L. Burkes, M.D.

2. Historic Synopsis in the Treatment of Colorectal Cancer
5-FU has anti-tumor activity
Biochemical modulation of 5-FU with LV 1989
HAI with FUDR  RR
Responses seen post bolus 5-FU with
infusional 5-FU
Adjuvant CT (5-FU/Lev or 5-FU/LV)
for colon cancer
Adjuvant CT + RT for rectal cancer
New drugs - CPT-11/Tomudex/Oxaliplatin
MTD – Cetuximab; Bevacizumab;
Panitumumab

3. Adjuvant Therapy for Stage II Colon Cancer: Yes, No and Maybe So

4. Why is the Situation in Stage II Colon Cancer Less Clear than Stage III
DFS and survival difference is small – relatively low activity of adjuvant treatment
High patient numbers required to show a difference
Stage II is a heterogeneous disease for
Clinical factors
Pathological factors
Molecular factors
Most trials were not stratified for these factors

5. Why is Adjuvant Therapy Effective in Stage III but not Stage II Disease: The Numbers
To detect a 2% survival difference between Rx and controls (90% power with significance level of .05) would require a sample size of 9680 pts per group
To detect an absolute risk reduction of 2.5% at 3 yrs and 4% at 5 (85% & 75% survival) would require a study of 8000 and 4700 pts respectively
Benson JCO 22:3408, 2004

6. Stage II Colon Cancer: Poor Prognostic factors
Inadequate staging
Clinical/pathological features
Molecular/enzymatic factors

7. Poor Prognostic Factors: Inadequate Staging
Variability of the number of lymph nodes sampled
Recent reports have independently recommended that >10 lymph nodes (ideally >12) be examined to classify a colon cancer as truly N0
Intergroup adjuvant trial
National Cancer Data Base
JCO, 2003
Ann Surg Oncology, 2003

8. Clinical/Pathological Features: Subset Analysis for B2 Intergroup Study (7 year survival)
Covariate
Observation
5-FU/Lev
Adhesion
70%
82%
Invasion
64%
86%
Obstruction
58%
Perforation
51%
67%

9. Stage II a Heterogeneous Disease: Molecular Factors
Microsatellite instability – MSI-Hi > MSS (stg for stg)
MSI-H vs MSS with CT – ND
MSS with CT - ↑ survival
MSI-H with CT – ND (trend to  survival)
18q LOH
DNA ploidy
EGFR+
P53
Microarray gene expression profiling
???KRAS
Gryfe NEJM 342:69, 2000
Ribic NEJM 349:247, 2003
Watanabe NEJM 344:1196, 2001
Barrier JCO 24:4685, 2006

10. Other Prognostic Pathological Variables
Grade
Lymphovascular invasion
Perineural invasion
?Immune response – lymphocytic infiltrate confers a better prognosis; fibrosis a worse prognosis

11. Pooled Analysis of Fluorouracil-Based Adjuvant Therapy for Stage II and III Colon Cancer
3 factors predict prognosis
- nodal status – N0 vs N1-4 vs >5
- depth of invasion – T1/2 vs T3 vs T4
- grade – low vs high
Stage II - 17% relative reduction in risk of recurrence (4% ↑ in 5 yr DFS; 72% vs 76% but overall survival was 80% vs 81%)
Gill JCO 22:1797, 2004

12. Adjuvant on Line Depth of invasion Histologic grade
# of nodes involved
# of nodes examined
Derived tumor stage
Age
General health (# of comorbid conditions)
Treatment

13. 5-FU + Levamisole for Stage II/Dukes’ B2 Colon Cancer
Obs 5-FU/Lev n
RFS (7 yr) % % p=.1
OS (7 yr) % % p=.83
 recurrence by 31% (p=.1)
disparity secondary to:
- higher rates of non-colon ca deaths with CT
- salvage surgery
Moertel JCO 13: 2936, 1995

14. IMPACT B2 Adjuvant Trials (n=1016) (GIVI0, NCIC, FFCD, NCCTG, Siena) Pooled Analysis
5-FU/FA Control
(370/200)
EFS (5 yrs) % 73%
OS (5 yrs) % 80%
JCO 17:1356, 1999 (Lancet 345:939,1995)

15. NSABP Colon Trials 5 Year Survival

16. Cancer Care Ontario Practice Guidelines for Stage II Colon Cancer
August, 1997
31 RCT’s
3 meta-analysis
1 evidence-based consensus statement
Update: April, 2000
4 meta-analysis
New or updated reports on 19 RCT’s

17. Cancer Care Ontario Practice Guidelines for Stage II Colon Cancer
Adjuvant therapy is not recommended
Patients with high risk factors have a poorer prognosis and adjuvant CT could be considered
- bowel obstruction
- tumor adhesion
- invasion
- perforation
- aneuploidy
Figueredo Ca Prev Control 1: 379, 1997
CCOPGI: Full Report – April, 2000

18. Systematic Review from the CCO Program in Evidence-Based Care’s GI Disease Site Group: Conclusions
No compelling evidence to use systemic adjuvant therapy.
There probably is a small benefit that present trials have yet to detect as significant.
Additional investigation of newer therapies and more mature data from the available trials should be pursued.
Figueredo JCO 22:3395, 2004

19. Conclusions Regarding Adjuvant Therapy: ASCO Guidelines
Adjuvant therapy for low-risk stage II colon cancer is not supported by randomized controlled trials.
Adjuvant therapy for hi-risk stage II disease is recommended - ? regimen.
Benson JCO 22:3408, 2005

20. Adjuvant CT vs Observation: QUASAR Gray PASCO 23:246(3501), 2004
FUFA Obs
n=3239
Stg II 92% 92%
Colon 71% 71%
5 yr - RR 22.2% %
- Surv % %

21. Adjuvant Immunotherapy with MoAb 17-1A for Stage II CRC: CO
Adjuvant Immunotherapy with MoAb 17-1A for Stage II CRC: CO.14 (CALGB 9581) Colacchio PASCO 23:251(3522), 2004
17-1A
No Difference pts (13% recurrence in each arm; 86% & % survival)
Obs

22. Who Should be Considered for Adjuvant FOLFOX: Stage II Patients Chua PGI ASCO: 202 (#237), 2005
Hi-Risk - T4, venous invasion, perforation, obstruction
All pts received LV/5-FU
Hi-risk Low-risk Stage III
DFS - 3 yr % %
OS - 5 yr 77.6% % %
Conclusions:
Pts with hi-risk stage II had a worse DFS and OS than the low-risk group
Recommend FOLFOX for hi-risk stage II

23. FULV vs FLOX for Stage II or III Colon Cancer: NSABP C-07 Wolmark PASCO 23&26: 246s/179s (3500/4005), 2005/2008
FULV FLOX
N % 28.9%
N % 44.8%
N> % 25.6%
Neuro - all gr % 1 yr)
- gr % 1 yr)
Oxali dose mg/m2
(1020 in MOSAIC)

24. FULV vs FLOX for Stage II or III Colon Cancer: NSABP C-07 Wolmark PASCO 26:179s (4005)2008
DFS - 3 yr
- 5 yr
71.5%
64.2%
76.1%
69.4%
OS - 5 yr
- 6 yr
78.3%
73.5%
80.3% (p=.06)
77.7% (HR=.85)
Surv after recur
22.2 mo
17.6 mo
Global test for interaction between stage and Rx was not significant (p = .7)

25. Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC Trial Andre NEJM 350:2343, 2004; de Gramont PASCO 23:246 (3501), 2005 and PASCO 25:#4007, 2007

26. LV5FU2 FOLFOX4 1123 1123 Stage II/III 40%/60% 40%/60%
Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC Trial Andre NEJM 350:2343, 2004; deGramont PASCO 23:246 (3501), 2005
LV5FU FOLFOX4
Stage II/III 40%/60% 40%/60%
Mean # cycles
DI FU % %
- Oxali %

27. MOSAIC Trial: 5 Year DFS de Gramont PASCO 25:#4007, 2007
LVFU2
FOLFOX4
All pts
67.4%
73.3%
Stage III
58.9%
66.4%
Stage II
79.9%
83.7%
Hi-risk stage II
(576)
74.9%
82.1%
Low-risk stage II
(323)
86.3%
89.1%

28. MOSAIC Trial: 6 Year Survival de Gramont PASCO 25:#4007, 2007
LV5FU2
FOLFOX4
All pts
76%
78.6%
HR = .85; p = .057
Stage III
68.6%
73%
HR = .8; p = .029
Stage II
86.8%
86.9%
HR = 1; p = .996

29. MOSAIC Trial: Conclusions
DFS benefit seen at 3 yrs is maintained at 5 yrs
At 6 years there is no survival benefit for stage II pts
Despite a DFS benefit with F4 for hi-risk stage II pts this did not translate into a survival benefit
There was no increase in 2nd cancers
There is continued recovery in peripheral neuropathy but 15% of pts still had residual PN at 4yrs (.7% gr 3; 2.8% gr 2; 12% gr 1)

30. DFS (3 yr) vs OS (5 yr) as a Primary Endpoint for Adjuvant Therapy for CRC Sargent PASCO 23:249s (3512), 2005/JCO 23:8564, 2005
43 Rx arms; n = 20,898 pts
M:F = 54:46
Stg II:III = 34:66
74% of recurrences in 1st 3 yrs
3 yr DFS & 5 yr OS – cc = .92 for stg III but only .65 for stg II
DFS excellent predictor of OS at 5 yrs (stg III)
ODAC voted 15 to 0 to accept as a surrogate marker (Pazdur)

31. Microsatellites Short, tandemly repeated DNA sequences
Detected at the molecular level using genomic DNA from either fresh or paraffin-fixed CRC tissues
Insertion or deletions of nucleotides within repeated sequences of DNA = Microsatellite Instability
Frequent alterations in DNA sequence length = MSI-H
MSI is due to defective mismatch repair genes

32. dMMR as a Predictive Marker for Lack of Benefit from 5-FU based Adjuvant Chemotherapy
Sargent PASCO 26:180s (#4008), 2008

38. Summary of Adjuvant Therapy for Stage II Colon Cancer: DFS
Moertel IMPACT Gray Mosaic
7 yr yr yr yr
Obs CT Obs CT Obs CT LV5FU2 F4
71% % % 76% % % % %

39. Conclusions: Stage II
Prospective clinical trials and meta-analyses have not yet shown a benefit for adjuvant chemotherapy.
Present guidelines have recommended against the use of such treatment in “standard risk” patients.
The use of adjuvant therapy in subsets of stage II pts with ominous clinical, pathological or molecular characteristics appears reasonable although the value of this strategy has not been prospectively validated and the regimen to use is controversial.

40. Stage III Disease

41. Intergroup Trial of Levamisole/5-FU for Stage III Colon Carcinoma (F/U > 5 yrs, med 6.5)

42. IMPACT Trial: Adjuvant 5-FU/FA (GIVI0, NCIC, FFCD)

43. IMPACT Trial: Adjuvant 5-FU/FA (GIVI0, NCIC, FFCD) - cont’d.
decrease recurrence by 33%
decrease mortality by 22%
borderline EFS & none for OS for Dukes’ B
Lancet 345: 939, 1995

44. 6 months of 5-FU + Leucovorin (LD/HD) became the standard
5-FU/LV vs FU/Lev vs 5-FU/LV/Lev: Low dose vs Hi-dose and 6 months vs 12 months
6 months of 5-FU + Leucovorin (LD/HD) became the standard
adjuvant treatment

45. NSABP C04: 5-FU/LV vs FU/Lev vs 5-FU/LV/Lev
DFS (5 yr) OS (5 yr)
5-FU/LV 64% 74%
5-FU/LV/Lev 64% 72%
5-FU/Lev 60% %
5-FU/LV has a DFS & S advantage in Dukes’ B & C
Wolmark PASCO 15: (460), 1996

46. NCCTG + NCIC-CTG Adjuvant Trial
RFS (4 yrs) S (4 yrs)
5-FU/Lev/LV x
5-FU/Lev x
5-FU/Lev/LV x
5-FU/Lev x p<.005
6 mo 5-FU/Lev inferior to 6 mo 5-FU/Lev/LV
12 mo of CT offers no advantage over 6 mo
6 mo 5-FU/Lev/LV associated with best S but not superior to 12 mo
O’Connell PASCO 15: (478), 1996

47. 5-FU/FA Adjuvant Trial: NCCTG, SWOG, ECOG, CALGB

48. Inter Group Trial - INT 0089 Comparison LDLV vs HDLV Lev vs LDLV
Lev vs HDLV
LDLV vs LDLV/Lev
Lev vs LDLV/Lev
DFS (5 yr) OS (5 yr)
60 vs vs 65
56 vs vs 66
56 vs vs 65
59 vs vs 67
56 vs vs 67
(p=.014) (p=.074)

49. Inter Group Trial - INT 0089
only difference is 5-FU/Lev vs 5-FU/LDLV/Lev
5-FU/LDLV/Lev not superior to 5-FU/LDLV
Levamisole is not necessary
6 months of 5-FU + LV (LD/HD) should be standard adjuvant treatment
Haller PASCO 17: (982), 1998

50. 5-Fluoruracil + Edrecolomab (17-1A Ab) as Adjuvant Therapy for Stage III Colon Cancer Fields PASCO 21:128a (508), 2002
5-FU + Ab 5-FU
(924) (915)
3 yr S 81.6% 78.9% p=.023
Colon Ca S 84.5% p=.007
DFS 67.5% 66.6% ND
No  toxicity
Low incidence of neutropenia
<1% Rx-related deaths

51. Capecitabine vs Mayo in Stage III CRC: X-ACT Study Twelves NEJM 352: 2696, 2005; GI ASCO #274, 2008
Cape Mayo
T1/2 10% 10%
T % 76%
T % 14%
3 yr - DFS % 56.7%
- RFS % 61.9%
- OS % 68.4%
Toxicity - H/F ↑
- Diarrhea ↓
- Stomatitis ↓
- Neutr ↓
Conclusions:
↑ RFS
Trend to ↑ DFS & OS benefit
↑ safety

52. X-ACT Trial: Survival Data

53. UFT vs FULV (Roswell) in Stage II & III CRC: NSABP CO6 Wolmark PASCO 23:#3508, 2004
Roswell UFT
II % 47%
III % 54%
N % 37%
N % 16%
RFS % 74.5%
DFS % %
OS % 78.7%
Diarrhea % 29%
QOL ND
Sx distress ↓
Conclusion
Equitoxic
Equivalent
UFT not available in N.A.

54. Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC Trial Andre NEJM 350:2343, 2004; de Gramont PASCO 23:246 (3501), 2005 and PASCO 25:#4007, 2007

55. LV5FU2 FOLFOX4 1123 1123 Stage II/III 40%/60% 40%/60%
Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC Trial Andre NEJM 350:2343, 2004; deGramont PASCO 23:246 (3501), 2005
LV5FU FOLFOX4
Stage II/III 40%/60% 40%/60%
Mean # cycles
DI FU % %
- Oxali %

56. MOSAIC Trial: 5 Year DFS de Gramont PASCO 25:#4007, 2007
LVFU2
FOLFOX4
All pts
67.4%
73.3%
Stage III
58.9%
66.4%
Stage II
79.9%
83.7%
Hi-risk stage II
(576)
74.9%
82.1%
Low-risk stage II
(323)
86.3%
89.1%

57. MOSAIC Trial: 6 Year Survival de Gramont PASCO 25/26:#4007, 2007/08
LV5FU2
FOLFOX4
All pts
76%
78.6%
HR = .85; p = .057
Stage III
68.6%
73%
HR = .8; p = .029
Stage II
86.8%
86.9%
HR = 1; p = .996
Alive with Recurrence
7.8%
6.1%
Time from Recur to Death
24 mo
21 mo

58. MOSAIC Trial: Conclusions
DFS benefit seen at 3 yrs is maintained at 5 yrs
There is a 6 yr OS benefit for stage III pts
There was no increase in 2nd cancers
There is continued recovery in peripheral neuropathy but 15% of pts still had residual PN at 4yrs (.7% gr 3; 2.8% gr 2; 12% gr 1)

59. FULV vs FLOX for Stage II or III Colon Cancer: NSABP C-07 Wolmark PASCO 23: 246s (3500), 2005
FULV FLOX
N % 28.9%
N % 44.8%
N> % 25.6%
Neuro - all gr % 1 yr)
- gr % 1 yr)
Oxali dose mg/m2 (1020 in MOSAIC)
DFS – 3 yr % %
Global test for interaction between stage and Rx was not significant (p = .7)

60. FULV vs FLOX for Stage II or III Colon Cancer: NSABP C-07 Wolmark PASCO 26:179s (4005)2008
DFS - 3 yr
- 5 yr
71.5%
64.2%
76.1%
69.4%
OS - 5 yr
- 6 yr
78.3%
73.5%
80.3%
77.7%
Surv after recur
22.2 mo
17.6 mo
Global test for interaction between stage and Rx was not significant (p = .7)

61. MOSAIC vs CO.7: 5 year Survival: Stages II/III
Study
DFS ∆ HR
MOSAIC
81.3%
2.2%
.85
CO.7
80.3%
2.0%

62. Comparison of Adjuvant Trials
Moertel IMPACT X-ACT MOSAIC
Regimen Lev/5-FU LV/5-FU Cape FOLFOX
DFS (3yr) % % 64.2% %

63. Role for Adjuvant Irinotecan
Adjuvant FL (Roswell) vs IFL in Stage III CRC: CALGB (CO.15)
FOLFIRI vs LV5FU2 in Stage III Colon Cancer: PETACC 3
Adjuvant LV5FU2 vs FOLFIRI for Stage III (hi-risk) Colon Cancer: ACCORD-2
All negative studies – no role for adjuvant irinotecan
Saltz PASCO 23: 246 (3500), 2004
van Cutsem PASCO 23:3 (8), 2005
Ychou PASCO 23: 246s (3502), 2005

64. DFS (3 yr) vs OS (5 yr) as a Primary Endpoint for Adjuvant Therapy for CRC Sargent PASCO 23:249s (3512), 2005
43 Rx arms; n = 20,898 pts
M:F = 54:46
Stg II:III = 34:66
74% of recurrences in 1st 3 yrs
3 yr DFS & 5 yr OS – cc = .92 for stg III but only .65 for stg II
DFS excellent predictor of OS at 5 yrs (stg III)
ODAC voted 15 to 0 to accept as a surrogate marker (Pazdur)

65. Time-Dependent Patterns of Failure and Treatment Benefit from Adjuvant Therapy for Resectable Colon Cancer: Lessons from the 20,800-pt ACCENT database Sargent PASCO 25:#4008, 2007

66. ACCENT: Conclusions

67. ACCENT: Survival from Recurrence O’Connell PASCO 25:#4009, 2007

68. PASCO 26:179s (#4007), 2008

69. MOSAIC:Long Term Follow Up
DFS OS
Difference
3 yr
5.3
1.1
4.2
4 yr
6.6
1.6 5
5/6 yr
5.9
2.6
3.3

70. Extended survival after recurrence ’s the DFS and OS relationship

73. How to Follow Patients Post Adjuvant Therapy
Examine and do BW including CEA every 3 months (pre-op CEA)
CT chest, abdomen and pelvis every 6 months x 3 years and then annually x 2 years
Colonoscopy at 1 year post op and then every 3 years if no polyps
ASCO guidelines (Desch JCO 23:8512, 2005)

74. Adjuvant Therapy of Stage III Colon Cancer: 3 year DFS (equates with 5 year survival)

75. Rectal Cancer

78. Post-op CT +/- RT for Rectal Cancer
Trial Rx N
LF (%)
DFS (%)
OS (%)
GITSG S
202 24 46 45 RT 20 52
FU/Me 27 54 56
RT+CT 11 70 59
NCCTG
204 25 38 48
RT+FU/Me
13.5 58
R-01
555 30 43 16 35 41
MOF 21 53
R-02 CT
694 13 50 8
NEJM 312:1465,1985; NEJM 324: 709,1991; JNCI 80:21,1988; JNCI 92:388,2000

79. Adjuvant Postoperative 5-FU CT/RT for Rectal Cancer: Intergroup 0114
1696 pts
(RT) - 5-FU, FULV, FU/Lev, FU/LV/Lev
No advantage to any treatment compared with bolus 5-FU alone
↑ local control and survival for node neg stage II disease with > 13 nodes dissected
 GI toxicity with 3 drugs
No benefit of Levamisole
Tepper JCO 15/20:2030/1744, 1997/2002

80. Swedish Rectal Cancer Trial (T1-3)
Pre-op RT Surgery
+ Surgery
Local recurrence % % p<.001
OS (5 yr) % % p=.004
Cancer SS (9 yr) % % p=.002
NEJM 336: 980, 1997

81. Dutch TME Study Local Recurrence TME RT  TME 2 year 8.2% 2.4% 5 year
12% 6%
Perioperative morbidity - 29% wound complications
- 12% post op leaks
- lack of downstaging
NEJM 345:638,2001; Eur J Ca 38:919,2002; JCO 19/20:1976/817,2001/2002

82. Pre-operative vs Post-operative Therapy in Rectal Cancer: NSABP R03 Roh PASCO 23:247(3505), 2004
Pre-op Post op
OS (3 yrs) 74% 66%
DFS 64% 53%
RFS 77% 70%
cCR 25% -
pCR 17% -
SS 48% 39%
cCR correlated with DFS & OS
Trend to ↑ survival with preop CT/RT

83. German Rectal Study (CAO/ARO/AIO-94): Pre-op vs Post-op CI 5-FU/RT then 5-FU x 4
5 year outcome
Preop
Postop
Acute toxicity
27%
40%
Late toxicity
14%
24%
pCR 8%
Sphincter preserv
39%
19%
Local Recurrence 6%
13%
Distant RR
36%
38%
DFS
65%
68% OS
74%
76%
Sauer NEJM 351:1731, 2004

84. Pre-op RT + 5-FU/LV in T3-4 Rectal Cancer: FFCD 9203 Gerard PASCO23:246s(3504), 2005
RT/CT N
363
370
cCR
2.6%
5.7%
Sphincter preser
51.7%
52.6%
pCR
3.7%
11.7%
Local Failure
16.5% 8%
5 yr DFS
56%
59%
5 yr OS
66.6%
67.8%

85. Pre-op RT in Rectal Cancer: Effect and timing of additional CT: EORTC 2291 Bosset PASCO 23: 247s (3505), 2005
N = 1011
Preop RT
Preop RT/CT
Postop CT
No postop CT
pCR 5%
11% -
Sphinter preserv
52.4%
56%
5 yr PFS
54.4%
67.1%
63.2%
5 yr OS
64.8%
65.6%
58.1%
52.2%
5 yr LR: RT vs RT/CT vs RT-CT vs RT/CT-CT
17.1% vs 8.7% vs 9.6% vs 7.6%

89. Standard of Care for Most Patients with Stage II/III Rectal Cancer
CI 5-FU 225 mg/m2/day or Xeloda
+ RT 
Surgery
FOLFOX x 8 cycles

90. Intermediate – T1,2/N1; T3/N0 Moderately High – T1,2/N2; T3/N1; T4/N0
Impact of T and N Stage and Treatment on Survival in Adjuvant Rectal Cancer: A pooled analysis of NCCTG, NSABP and INT 0114
Risk Groups
Intermediate – T1,2/N1; T3/N0
Moderately High – T1,2/N2; T3/N1; T4/N0
High – T3/N2; T4/N1; T4/N2
Gunderson JCO 22:1785, 2004

91. Rectal Cancer Pooled Analysis: 5 year OS Gunderson JCO 22:1785, 2004
Intermed
S + CT
84-85%
S + CT + RT
74-83%
Mod High
43-70%
44-80%
High
25-45%
29-57%

92. Molecular Assessment of Patients
Identify distinct clinical attributes
Identify pts who would benefit from adjuvant CT
Identify pts with such good prognosis CT-costs and complications could be avoided
Predicting chemo-responsiveness (adjuvant therapy)
Screening
Prevention

93. Questions
Do patients with MSS or MSI-H tumors have the same response to adjuvant/palliative chemotherapy?
Do all patients need chemotherapy?
Do different chemotherapy drugs have the same effects on different tumors?

94. Molecular Assessment of Patients: Prognostic factors
Microsatellite instability – MSI-Hi > MSS (stg for stg)
MSI-H vs MSS with CT – ND
MSS with CT - ↑ survival
MSI-H with CT – ND (trend to  survival)
18q LOH
DNA ploidy
EGFR+
P53
Microarray gene expression profiling
???KRAS
Gryfe NEJM 342:69, 2000
Ribic NEJM 349:247, 2003
Watanabe NEJM 344:1196, 2001
Barrier JCO 24:4685, 2006

95. Clinical Research Issues
Targeting the patient
Targeting the tumour
Define the role for targeted therapy
- Bevacizumab
- Cetuximab
- Panitumumab
Define the optimal duration of therapy
- Efficacy
- Toxicity
- Cost

96. Future Adjuvant Trials

97. CRC.2 (N0147)
Stage III  FOLFOX6 x Cetuximab

98. CRC.3 in Canada

101. Stage II/III Rectal Cancer Pre-op CT/RT
NCIC CRC.4/E5204
Stage II/III Rectal Cancer
Pre-op CT/RT
FOLFOX +
Bevacizumab
FOLFOX

102. Conclusions Regarding Adjuvant Therapy
Adjuvant therapy for low-risk stage II colon cancer is not supported by randomized controlled trials (Benson JCO 22:3408, 2005).
Adjuvant therapy for hi-risk stage II disease is recommended - ? Xeloda/FOLFOX.
Adjuvant CT with either FOLFOX or Xeloda for stage III colon cancer is standard practice.
Pre-op CT/RT for stage II & III rectal cancer followed by FOLFOX is the usual practice. In the post-op setting pts usually receive FOLFOX x 4  CT/RT  FOLFOX x 4.

103. Neoadjuvant FOLFOX4 for Potentially Resectable Liver Metastases: EPOC Trial Nordlinger PASCO 25: 2s (#5), 2007 R
ESECT ABL E
FOLFOX4 x 6  Surgery  FOLFOX4 x 6
(182)
Surgery alone
(182)
N = 364
Up to 4 liver metastases
No extrahepatic disease
No previous Oxaliplatin

104. 31 and 30 pts not resectable (F4/surgery):
11 ineligible in each arm 20 advanced disease
31 and 30 pts not resectable (F4/surgery):
- > 4 lesions or extrahepatic disease

105. EPOC Trial – cont’d FOLFOX4 182 Surgery 6 cycles 78.6% - RR - CR/PR
- SD/PD
3.8%/40.1%
35.2%/6.6%
OR (n/%)
Resected (n/%)
159/87.4%
151/83%
170/93.4%
152/83.5%
Complications
25.2%
15.9%
Biliary fistula (n) 12 5
Hepatic failure (n) 11 8
Intra-abdominal inf 2
Post-op deaths 1

106. EPOC Trial: Results CT Surg % 3 yr abs diff in PFS HR (CI) p-value
All pts
(ITT)
182
+7.2%
.79
( )
.058
All eligible pts
171
+8.1%
.77
(.6-1)
.041
All resected pts
151
152
+9.2%
.73
( )
.025
NB: primary endpoint was a PFS HR of .71
Irinotecan – Steatohepatitis (N/CASH)
Oxaliplatin – Sinusoidal/vascular damage

107. EORTC 40051: BOS Trial Remember the PACCE trial
? Data for F6 + Cetuximab