1. Challenging Cases in Cancer: Integration of Findings from ASCO 2007 Colorectal Cancer
Neoadjuvant Colorectal Cancer
Axel Grothey, MD
Senior Associate Consultant
Division of Medical Oncology
Mayo Clinic College of Medicine
Rochester, MN

2. Case 1: Neoadjuvant Therapy
54-year-old male with 6-months of weight loss and fatigue
Sees PCP and physical exam significant for liver edge palpable 2 cm below RCM
Hb 9.7 g/dL with MCV 75 µm³ (previously 90 µm³)
Stool guaiac positive

3. Case 1: Neoadjuvant Therapy
Referred to gastroenterologist for evaluation
CEA 25 ng/mL
Colonoscopy shows sigmoid mass
Biopsy adenocarcinoma with signet ring features
CT scan shows
5 hepatic lesions up to 4 cm in diameter (2 in left, 3 in right liver lobe)
Thickening of sigmoid colon with local node enlargement

4. Case 1: Neoadjuvant Therapy
Which treatment option would you recommend?
Surgery for primary, followed by chemotherapy
Surgery for primary and metastatic disease
Primary (neoadjuvant) chemotherapy followed by surgery

5. Case 1: Neoadjuvant Therapy
Which treatment option would you recommend?
Surgery for primary, followed by chemotherapy
Surgery for primary and metastatic disease
Primary (neoadjuvant) chemotherapy followed by surgery
Recommended approach

6. Pertinent Issues for Case 1
Optimal management of liver metastases
Primarily resectable metastases
Role of neoadjuvant therapy
Unresectable metastases
Optimal therapy to downsize metastases (“conversion” therapy)
Role of postoperative, adjuvant therapy

7. Liver Resection – New Perspective
Old:
Resectability determined
by “what comes out”
New:
Resectability determined
by “what stays in”

8. Future Liver Remnant Volume (FLR)60
Complications (%)
6/12
4/30
% FLR ≤ 20%
% FLR > 20% 50 40 30 20 10
P < .05
Abdalla EK. Arch Surg 2002; 137:675

9. Multimodality Management of CRC Liver Metastases
Neoadjuvant chemotherapy
Resectable liver metastases
Facilitate surgery
Obtain predictive and prognostic information
Early systemic therapy for poor-prognosis pts
Conversion chemotherapy
Unresectable liver metastases
Allow R0 resection via downsizing
Postoperative (adjuvant) chemotherapy
Hepatic arterial infusion (HAI)
Systemic treatment

10. Importance of Response to Neoadjuvant Therapy of Liver Metastases Prior to Resection
131 (of 441) patients with CRC and > 4 liver metastases underwent (mostly) FOLFOX-based neoadjuvant therapy
Survival outcome by response to chemotherapy
Response
Stabilization
Progression P
No. of patients
58 (44%)
39 (30%)
34 (26%)
Nodules (mean)
6.2
5.7
Hepatic recurrence
55%
77%
82%
1-yr survival
95%
92%
63%
5-yr survival
37%
30% 8%
<
Adam et al., Ann Surg 2004

11. Survival After Primary or Secondary Resection of Liver Metastases
Proportion Surviving 1 .9
Resectable (N = 425)
Initially non-resectable (N = 95) .8 .7
54% .6 .5
50%
34% .4
27% .3
34% .2
29%
19% .1 1 2 3 4 5 6 7 8 9 10
Survival Time (years)
Bismuth et al., 1996

12. Resectability Correlates with RR
Response Rate
0.9 .8 .7 .6 .5 .4
0.3
0.6 .3 .2 .1
0.0
Resection Rate
Studies with neoadj. focus
Phase III trials
Phase II trials
Folprecht et al., Ann Oncol 2005

13. Hepatic Arterial Infusion of Chemotherapy After Hepatic Metastasis
5-FU/LV
Randomized After Hepatic Resection
N=156
5-FU/LV + HAI FUDR
Combination Therapy
5-FU/LV P
2-yr OS (%)
86.0
72.0
.03
mOS (mo)
72.2
59.3 NS
2-yr recurrence-free survival (%)
90.0
60.0
<.001
2-yr risk of death
1.0
2.3x
.027
Median OS update 2005 (mo)
68.5
58.8
0.10
HAI FUDR = hepatic arterial infusion with floxuridine and dexamethasone.
Kemeny et al. N Engl J Med. 1999;341:2039
Kemeny et al. N Engl J Med 2005;352:734

14. EORTC 40983 - Perioperative FOLFOX in Resectable Liver Mets
RANDOMIZE
Surgery
FOLFOX4
6 cycles
(3 months)
N = 364 patients (09/00-07/04)
Aim: To demonstrate that chemotherapy combined with surgery is a better treatment than surgery alone
Primary endpoint: PFS (40% increase in median PFS (HR = 0.71) with 80% power and 2-sided significance level 5%)
Secondary endpoints: OS, resectability, response, safety
Nordlinger et al., ASCO 2007 Abstract LBA5

15. Complications of Surgery
Peri-op CT
Surgery
Postoperative complications*
40/159 (25.2%)
27/170 (15.9%)
Cardio-pulmonary failure 3 2
Bleeding
Biliary Fistula 12 5
(Incl output > 100 ml/d, >10d)
(9)
(2)
Hepatic Failure 11 8
(Incl. bilirubin>10 mg/dl, >3d)
(10)
(5)
Wound infection 4
Intra-abdominal infection
Need for reoperation
Other 25 16
Incl. postoperative death
1 patient
2 patients
*P = 0.04
Nordlinger et al., ASCO 2007 Abstract LBA5

16. Nordlinger et al., ASCO 2007 Abstract LBA5
Patient Flow
Informed consent
Randomized: 364
Pre & Postop CT 182
Surgery 182
Resectable on imaging 11
Ineligible 11
Started pre-op CT 171
Resected 151
Resectable at surgery
Resected 152
Preop cycles 1-6: 78.6%
Start postop CT: 63.2%
Postop cycles 1-6: 43.9%
Started postop CT 115
Nordlinger et al., ASCO 2007 Abstract LBA5

17. % absolute difference in 3-year PFS (Confidence Interval)
Results EORTC 40983
N pts CT
N pts Surgery
% absolute difference in 3-year PFS
Hazard Ratio
(Confidence Interval)
P-value
All patients
182
+7.2% (28.1% to 35.4%)
0.79 ( )
0.058
All eligible
Patients
171
+8.1% (28.1% to 36.2%)
0.77 ( )
0.041
All resected
151
152
+9.2% (33.2% to 42.4%)
0.73 ( )
0.025
MOSAIC: 3-yr DFS for stage III: +7.2%
Nordlinger et al., ASCO 2007 Abstract LBA5

18. Progression-free Survival in Eligible Patients
HR = 0.77; CI: , P = 0.041
Periop CT
28.1%
36.2%
+8.1% At 3 years
years 1 2 3 4 5 6 10 20 30 40 50 60 70 80 90
100 O N
Number of patients at risk:
125
171 83 57 37 22 8
115 74 43 21
Surgery only
Nordlinger et al., ASCO 2007 Abstract LBA5

19. Take-Home Messages EORTC 40983
Perioperative therapy with FOLFOX4 improves PFS (DFS) in patients with resectable liver metastases
With preoperative FOLFOX4 higher incidence of postoperative complications, but same operative mortality
Study never intended to answer question if ALL patients with resectable liver metastases should receive pre-operative chemo
 Trial provides first evidence in a prospective trial that chemotherapy in the context of resected stage IV disease provides PFS benefit

20. Case 2: Stage III Colorectal Cancer
62-year-old woman
History of hypertension, but otherwise healthy
Presents with GI bleeding, adenocarcinoma of descending colon identified
Patient undergoes laparoscopic colectomy
Pathology demonstrates T3N1 (2/15) M0 colon cancer, moderately differentiated and no evidence of lymphovascular invasion
Patient has healed well, discharged from the hospital in 5 days

21. Case 2: Stage III Colorectal Cancer
Which treatment option would you recommend?
5-FU/LV
Capecitabine
FOLFIRI
FOLFOX
Bolus 5-FU/LV and oxaliplatin (FLOX)
CAPOX (XELOX)
Other

22. Case 2: Stage III Colorectal Cancer
Which treatment option would you recommend?
5-FU/LV
Capecitabine
FOLFIRI
FOLFOX
Bolus 5-FU/LV and oxaliplatin (FLOX)
CAPOX (XELOX)
Other
Recommended approach

23. Case 2: Stage III Colorectal Cancer
Would you add a targeted agent to adjuvant chemotherapy? No
Yes, bevacizumab
Yes, cetuximab (or panitumumab)

24. Case 2: Stage III Colorectal Cancer
Would you add a targeted agent to adjuvant chemotherapy? No
Yes, bevacizumab
Yes, cetuximab (or panitumumab)
Recommended approach
No – Remains investigational in adjuvant setting

25. Pertinent Issues for Case 2
Relatively young patient, no serious comorbidities
Stage IIIB colon cancer T3 N1 (2/15)
Standard adjuvant therapy for stage III colon cancer?
Addition of biologics of any benefit?

26. History of Adjuvant Therapy for Colon Cancer
5-FU/lev superior to surgery alone
5-FU/LV superior to 5-FU/lev
6- and 12-month treatment cycles equivalent
Lev unnecessary
High-dose and low-dose LV equivalent
Monthly and weekly treatment equivalent
LV5-FU2 and monthly bolus equivalent
5-FU/LV superior to surgery alone
1990
1994
1998
2002
Moertel et al. Ann Intern Med. 1995;122:321.
Francini et al. Gastroenterol. 1994;106:899.
Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. Abstract
O’Connell et al. J Clin Oncol. 1998;16:295.
Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982.
Andre et al. Proc Am Soc Clin Oncol Abstract 529.

27. 3-Year DFS vs. 5-Year OS
May 05, 2004: ODAC recommends 3-yr DFS as new regulatory endpoint for FULL approval in adjuvant colon cancer
0.5
0.55
0.6
0.65
0.7
0.75
0.8
r = 0.88
3-Year DFS
5-Year OS
Sargent, et al. J Clin Oncol 2005;23:8664–8670.

28. MOSAIC: Study Design R FOLFOX4 LV5-FU2 N = 2246
Enrollment: Oct 1998=Jan 2001
(146 centers; 20 countries)
Completely resected colon cancer
Stage II, 40%; Stage III, 60%
Age years
KPS ≥ 60
No prior chemotherapy
FOLFOX4
(LV5-FU2 + oxaliplatin 85 mg/m²)
(N = 1,123) R
LV5-FU2
(N = 1,123)
Primary end-point: disease-free survival
Secondary end-points: safety, overall survival
LV5-FU2: Leucovorin 200 mg/m2 iv over 2 hours followed by 5-FUl 400 mg/m2 bolus and 5-FU 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days
FOLFOX4: LV5-FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1
André, et al. N Engl J Med 2004

29. MOSIAC: Disease-free Survival Stage II and Stage III Patients (ITT)
Disease-free Survival (months)
Probability
1.0
0.8
0.6
0.4
0.2
0.9
0.7
0.5
0.3
0.1 6 12 18 24 60 30 36 42 48 54
Events
FOLFOX /1123 (27.1%)
LV5-FU /1123 (32.1%)
HR [95% CI]: [0.68–0.93]
5.9%
P = 0.003
Data cut-off: June 2006
de Gramont A, et al. ASCO Abstract #4007

30. MOSIAC: Disease-free Survival Stage II and Stage III Patients
Months
HR [95% CI] P-value
Stage II [0.62–1.14]
Stage III [0.65–0.93]
FOLFOX4 stage II
LV5-FU2 stage II
FOLFOX4 stage III
LV5-FU2 stage III
Probability
1.0
0.8
0.6
0.4
0.2
0.9
0.7
0.5
0.3
0.1 6 12 18 24 60 30 36 42 48 54 66 72
3.8%
7.5%
P = 0.258
P = 0.005
Data cut-off: June 2006
de Gramont A, et al. ASCO Abstract #4007

31. MOSAIC - ASCO 2007: Disease-free Survival - Final Update
5-year DFS %
HR [95% CI]
P-value
FOLFOX4
LV5-FU2
ITT (overall population)
73.3
67.4
0.80
[0.68–0.93]
0.003
Stage III
66.4
58.9
0.78
[0.65–0.93]
0.005
Stage II
83.7
79.9
0.84
[0.62–1.14]
0.258
High-risk stage II N = 576
82.1
74.9
0.74
[0.52–1.06] —
Low-risk stage II N = 323
86.3
89.1
1.22
[0.66–2.26]
Data cut-off: June 2006
de Gramont A, et al. ASCO Abstract #4007

32. “High-risk” Stage II Colon Cancer
Clinico-pathological parameters (MOSAIC)
T4 tumors
Obstruction/perforation
Lymphatic or vascular invasion
Undifferentiated histology
Less than 10 (12) Ln examined
Molecular parameters
LOH 18q
MSS
Other?

33. MOSIAC: Long-Term Safety
Peripheral Sensory Neuropathy
Second Cancer
FOLFOX
5.3%
LV5-FU2
5.7%
Evaluable Patients
(N = 811)
Grade 0
84.3%
Grade 1
12.0%
Grade 2
2.8%
Grade 3
0.7%
Data cut-off: January 2007
de Gramont A, et al. ASCO Abstract #4007.

34. MOSIAC: Overall Survival Stage II and Stage III (ITT)
Overall Survival (months)
Probability
1.0
0.8
0.6
0.4
0.2
0.9
0.7
0.5
0.3
0.1 6 12 18 24 60 30 36 42 48 54 66 96 72 78 84 90
Events
FOLFOX /1123 (21.6%)
LV5-FU /1123 (24.8%)
HR [95% CI]: 0.85 [0.72–1.01]
2.6%
P = 0.057
Data cut-off: January 2007
de Gramont A, et al. ASCO Abstract #4007.

35. MOSIAC: Overall Survival Stage II and Stage III
FOLFOX4 stage II
LV5-FU2 stage II
FOLFOX4 stage III
LV5-FU2 stage III
Overall Survival (months)
Probability
1.0
0.8
0.6
0.4
0.2
0.9
0.7
0.5
0.3
0.1 6 12 18 24 60 30 36 42 48 54 66 96 72 78 84 90
HR [95% CI]
Stage II [0.71–1.42]
Stage III [0.66–0.98]
0.1%
4.4%
P = 0.996
P = 0.029
Data cut-off: January 2007
de Gramont A, et al. ASCO Abstract #4007.

36. Take Home Messages: MOSAIC
DFS benefit for FOLFOX is maintained over 5 years
Significant OS benefit for stage III, but NOT for unselected stage II patients
“High-risk” stage II with trend toward better DFS with FOLFOX, but clinical consequence unclear
No increased rate of secondary cancers, but more deaths from cancer in FOLFOX group (21 vs.11)
Even 4 years after FOLFOX, 3.5% of patients still have grade 2/3 neurotoxicity (+12% grade 1)
 FOLFOX is standard adjuvant therapy for stage III and can be considered for high-risk stage II CC

37. R NSABP C-07 x3 Rest Rest FU N = 2407 500 RP LV 500 FU 500 LV 500 FLOX
Endpoint
3-yr DFS
OHP 85
2hr
Week
30% stage II
Kuebler et al. J Clin Oncol 2007

38. NSABP C-07: DFS
Kuebler et al. J Clin Oncol 2007

39. NSABP C-07: HR DFS
Kuebler et al. J Clin Oncol 2007

40. Cross-Study Comparison Toxicity: MOSAIC/C-07
FOLFOX 4
(MOSAIC)
FLOX
(C-07)
Gr 3-4 Neutropenia
41%
(2% neut. fever)
4% (?)
Gr 3-4 Diarrhea
11%
38%
Gr 3-4 Neuro (cum oxali)
12.4% (1,020 mg/m2)
8.4% (765 mg/m2)
All Cause Mortality
0.5% 1%

41. X-ACT Trial in Adjuvant Treatment of Dukes’ C Colon Cancer
1° endpoint: disease-free survival (DFS)
Chemo-naïve
Dukes C,
resection ≤ 8 weeks
Capecitabine
1250 mg/m2 twice daily, d 1-14, q21d
N = 1 004
Bolus 5-FU/LV
5-FU 425 mg/m2 plus LV 20 mg/m2, d 1-5, q28d
N = 983
24 weeks
Twelves et al. NEJM 2005

42. Log-rank P = 0.0526 HR = 0.87 (95% CI: 0.75-1.00)
X-ACT Trial: DFS
1.0
0.8
0.6
0.4
0.2
Capecitabine (N = 1 004)
5-FU/LV (N = 983)
Absolute difference
at 3-years: 4%
Estimated probability
Log-rank P = HR = 0.87 (95% CI: )
Median follow-up 3.8 yrs
Years
Twelves et al. NEJM 2005

43. What is the Standard Adjuvant Therapy for Colon Cancer ?
FOLFOX is standard adjuvant therapy for stage III and can be considered in high-risk stage II colon cancer
FLOX validates adjuvant oxaliplatin, but too toxic (diarrhea)
Capecitabine for those patients who are not considered candidates for oxaliplatin
Irinotecan-based combinations are NOT options in the adjuvant setting
XELOX data eagerly awaited (ASCO 2008?)
Bevacizumab and cetuximab are under investigation

44. Ongoing U.S. Cooperative Group Trials Adjuvant Therapy of Colon Cancer
Intergroup N0147
mFOLFOX6 6m
Stage III colon cancer (N = 2,300)
Revised 5/05
mFOLFOX6 6m + cetuximab 6m
NSABP C-08
mFOLFOX6 6m
Stage II/III colon cancer (N = 2,400)
mFOLFOX6 6m + bevacizumab 12m

45. ASCO 2007 – Colorectal Cancer Commentary