1. Trips of Erodotus, 600 BC
Colorectal Cancer: State of the
Art
G Pentheroudakis
Assistant Professor of Oncology
Ioannina University Hospital

2. Advanced Colorectal Cancer
1. Most active combinations
2. Incorporation of targeted agents and use
of biomarkers
3. How to devise a rational treatment
strategy

7. Median overall survival correlates with the % of patients
who receive all 3 drugs in the course of their disease
Infusional 5-FU/LV + Oxaliplatin
22
Infusional 5-FU/LV + Irinotecan
21
Bolus 5-FU/LV + Irinotecan
Median OS (months)
20 Irinotecan + Oxaliplatin
19
18
17
16
P=.0008
15
14
13
0 10 20 30 40 50 60 70 80 90
% of Patients With 3 Drugs
Grothey et al. J Clin Oncol. 2004;22;1209-1214

8. Signal transduction via KRAS
Normano N, Tejpar S, Van Cutsem E, Ciardiello F. Nature Reviews Oncology 2009

9. Select the
patients who
will benefit!

10. CRYSTAL: study design Cetuximab + FOLFIRI
Cetuximab: 400mg/m² week 1 and
then 250 mg/m² weekly (starting
week 2)
Modified FOLFIRI: irinotecan
180mg/m² + 5-FU/FA (simplified
n=608 de Gramont regimen) every 2 weeks
EGFR-expressing
metastatic CRC R
n=609 FOLFIRI
Modified FOLFIRI: irinotecan
Primary endpoint: PFS 180mg/m² + 5-FU/FA (simplified de
Secondary endpoints: Median OS, Gramont regimen) every 2 weeks
RR and DCR, Quality of life, Safety

11. 1st-line treatment: OS, PFS, RR
CRYSTAL (KRAS wt) 1.0
1.0 20 23.5
ERBITUX + FOLFIRI
ERBITUX + FOLFIRI
0.8 (n=316) 0.8 8.4 9.9 (n=316)
FOLFIRI (n=350)
FOLFIRI (n=350)
0.6 0.6
HR=0.696
PFS
HR=0.796
OS
0.4 0.4
0.2
0.2
0.0
0 6 12 18 24 30 36 42 48 54 0.0
0 4 8 12 16 20
Time (months) Time (months)
70 p<0.0001
60
Response rate (%)
50 57.3
40
30
39.7
20
10
0
FOLFIRI ERBITUX
(n=350) + FOLFIRI
(n=316)
Van Cutsem E, et al. J Clin Oncol (in press)

12. ABS 3510
[TITLE]

13. [TITLE]

14. COIN trial in 1st-line mCRC
Continuous OxMdG/XELOX
+ ERBITUX
(400 mg/m2 day 1, then
Patients with mCRC;
no prior CT for advanced disease; 250 mg/m2 weekly)
R
fit for combination CT;
no prior testing for EGFR status
Continuous OxMdG/XELOX
Primary endpoint
• OS in KRAS wt
OxMdG: 2-weekly IV FA 175 mg,
oxaliplatin 85 mg/m2 over 2 h,
Secondary endpoints IV bolus 5-FU 400 mg/m2,
• OS in KRAS mt; KRAS, NRAS, BRAF wt; 5-FU 2400 mg/m2 infusion over 46 h via ambulatory pump
(mFOLFOX)
or any mutant XELOX: 3-weekly IV oxaliplatin 130 mg/m2 over 2 h,
• PFS oral capecitabine 1000 mg/m2 bd for 2 weeks
(reduced to 850 mg/m2 for toxicity)
• Overall response
• Quality of life
• Health economic evaluation Maughan T, et al. ECCO-ESMO 2009 (Abstract No. 6LBA)

15. COIN: Results in patients with
KRAS wt CRC
Arm B
Arm A OxMdG/XELOX
OxMdG/XELOX + ERBITUX
(n=367) (n=362) p-value
Median OS, months 17.9 17.0 0.68
Median PFS, months 8.6 8.6 0.6
ORR at 12 weeks, % 50 59 0.015
Maughan T, et al. ECCO-ESMO 2009 (Abstract No. 6LBA)

16. Summary of 3 studies: PFS
Patients with KRAS wt tumors
Study Hazard ratio (95% CI)
CRYSTAL (n=666) 0.70 (0.56–0.87)
Infusional 5-FU OPUS (n=179) 0.57 (0.38–0.86)
COIN OxMdG (n=244) 0.77 (0.59–1.01)
Capecitabine COIN XELOX (n=485) 1.06 (0.88–1.28)
0.5 0.75 1.0 1.25
Benefit under cetuximab Benefit under CT alone
Van Cutsem E, et al. J Clin Oncol 2010;28 (Suppl. 15):Abstract No. 3570;
Bokemeyer C, et al. ASCO GI 2010 Abstract No. 428;
PFS, progression-free survival Maughan T, et al. ASCO GI 2010 Abstract No. 402

21. BEVACIZUMAB: 1st-line PFS +
OS with XELOX/FOLFOX4 –
NO16966
Median PFS Median OS
8.0 vs 9.4 months 19.9 vs 21.2 months
1.0 HR=0.83 (p=0.023) 1.0 HR=0.89 (p=0.0769)
XELOX/FOLFOX4 + XELOX/FOLFOX4 +
Avastin Avastin
0.8 XELOX/FOLFOX4 + 0.8 XELOX/FOLFOX4 +
placebo placebo
Survival estimate
PFS estimate
0.6 0.6
0.4 0.4
0.2 0.2
8.0 9.4 19.9 21.2
0 0
0 5 10 15 20 25 0 6 12 18 24 30
Months Months
Saltz, et al. WCGC 2007

24. Treatment Strategy: Define your target
Treatment
Clinical situation What is needed?
intensity
• liver (± lung) metastases
Maximal tumor-
• potentially resectable
shrinking required Upfront
combination:
• multiple metastases multidrug
• rapid progression Control of regimens
• tumor related symptoms progressive disease
• (risk for) deterioration
• unresectable metastases Tumor shrinkage less Start with
• no option for resection relevant single agent
• no symptoms or risk for Control of further Sequential
rapid deterioration progression approach or
• comorbidity Prevention from doublets
toxicity
Expert discussion ESMO/WCGIC Barcelona june 2009

25. Adjuvant therapy
1. Optimal adjuvant chemotherapy regimens
2. To treat or not to treat stage II CRC?
3. Incorporation of targeted agents in the
adjuvant setting

26. 2004 – 2005
THE MOSAIC
STUDY
N=2246
FOLFOX4: LV5FU2 + Oxaliplatin 85mg/m²
Stage II (40%)
R / III (60%)
colon cancer
LV5FU2
Every 2 weeks, 12 cycles of treatment
Primary end-point: disease-free survival (non-colorectal Ca were
disregarded)
T staging was a stratification factor
N.E.J.M 350:2343-
51, 2004

27. OS Updated
André T, et al. J Clin Oncol 2009;27:3109-16.

28. X-ACT STUDY
Dukes’ C colon
Capecitabine
1250 mg/m2 bid,
d1–14, q21d
n = 1004
Randomize 24 weeks N=1987
Bolus 5-FU/LV
5-FU 425 mg/m2 plus
LV 20mg/m2, d1–5, q28d
n = 983
Jim Cassidy, Proc. ASCO 2004

29. DFS
1.0 3-year
Capecitabine (n=1004) 64.2%
5-FU/LV (n=983) 60.6%
Estimated probability
0.8 HR = 0.87 (95% CI: 0.75–1.00)
p=0.0528
0.6
0.4
0 1 2 3 4 5 6
Years
Significantly fewer adverse effects with capecitabine

30. IS ADJUVANT TREATMENT
INDICATED IN STAGE II
COLON CANCER ?
Ioannina: Promenade in the
Old Town

31. Adjuvant tx in Stage II
CRC?
 Lower rate of recurrence, better survival in stage II CRC
patients. There is no international consensus
 Recent meta-analysis found no significant survival
advantage.
Cochrane meta-analysis of all RCT 1980-2007
RR 0.96 for death (95% CI 0.88-1.05)
Cochrane Database Syst Rev 2008
 QUASAR Uncertain Indication Trial:
FU/LV vs observation, median FU 4.6 years.
Reduced recurrence ( RR 0.78, p= 0.001)
Improved survival ( RR 0.83, p= 0.002)
[ JCO 2004 abtract]
 Probably the same relative benefit, but small absolute
benefit.

33. 18-Gene signature for stage II
CRC
 Selection of 18 genes ( mRNA RT-PCR) from four
NSABP adjuvant studies
 Validation in 1436 patients (QUASAR study: 5FU
vs observation), median FU 6.6 years.
 Low Recurrence Score: 8-10% risk of relapse
 High Recurrence Score: 20-25% risk of relapse
 HR 1.98, p=0.01

34. Clinical application
 QUASAR Independent Predictors of stage II CRC
patient outcome: T4, MSI, Oncotype DX
 Stage II, T3, MSI-H: No adjuvant treatment (relapse
risk<5%)
 Stage II, T4: Adjuvant treatment
 Stage II, T3, MSI-L (75% of stage ΙΙ):
ONCOTYPE DX COLON CANCER ASSAY?

35. Goldberg RM et al.
Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in
patients (pts) with resected stage III colon cancer (CC):
NCCTG Intergroup phase III trial N0147

36. Goldberg RM, Sargent DJ, Thibodeau SN, et al. Adjuvant mFOLFOX6 plus or minus
cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon
cancer (CC): NCCTG Intergroup phase III trial N0147. Abstract 3508.
Wild-Type KRAS Mutant KRAS
mFOLFOX6 mFOLFOX6 + mFOLFOX6 mFOLFOX6
Outcome (n = 902) Cetuximab (n = 374) +
(n = 945) Cetuximab
(n = 343)
3-yr DFS, % 75.9 72.3 67.2 64.2
HR (95% CI) 1.2 (0.96-1.50) 1.2 (0.9-1.6)
P value .22 .13
3-yr OS, % 87.8 83.9 88.0 80.4
HR (95% CI) 1.3 (0.96-1.80) 1.5 (0.9-2.3)
P value .13 .12

37. [TITLE]

38. [TITLE]

39. Comments
• Bev delays relapse, does not prevent it
• No evidence though that Bev alters biology of
disease, no OS difference in CR08.
• INTERPRETATION: The relapses that did
not occur during the first 1-1.5 years on
Bev, occurred later on along with the steady
rate of relapse over time.