1. “Continuum of care” en cáncer de colon metastásico no curable
Mauricio Lema Medina MD
Clínica de Oncología Astorga – Clínica SOMA – Medicáncer
Medellín, Colombia 1

2. Quimioterapia
A qué llegamos? 2

3. Fluoropirimidines en mCRC
No cambio en la supervivencia mediana con diferentes esquemas
Supervivencia mediana: ~ 12 meses
Regimen
Respuesta, %
5-FU en bolo
7-15
5-FU en infusión
20-30
5-FU/LV
Mayo, Roswell Park
de Gramont (LV5-FU2)
AIO (cada semana, 24-hour infusion)
12-35
28-33
25-44
Capecitabina
20-25
5-FU, fluorouracil; AIO, Arbeitsgemeinschaft Internische Onkologie; LV, leucovorin.
Grothey A, et al. J Clin Oncol. 2005;23:

4. IFL vs FOLFOX vs IROX (N9741)
diseño
IFL (n=264)
FOLFOX
(n=267) R
Bolo (IFL) vs infusión (FOLFOX)
n=795
IROX
(n=264)
Primary endpoint: PFS
Goldberg et al, JCO 2004

5. N9741: Sanoff HK. J Clin Oncol 26:5721-5727.

6. N9741 Resultados IFL FOLFOX IROX n 264 267 RR (%) 31 45 35 PFS (m) 6.9
8.7
6.5
OS (m) 15
19.5
17.4 p
0.0001
Primum non nocere 2 yrs post bev
Goldberg et al, JCO 2004

7. Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design
Initial design
FOLFIRI (n=144)
mIFL
(n=141) R
n=430
XELIRI
(n=145)
Feb 2003 – April 2004
Primary endpoint: PFS
* Celecoxib data not shown
Fuchs et al, JCO 2008
Courtesy of: Paulo Hoff

8. BICC-C Study: FOLFIRI vs mIFL vs CapeIRI
Progression-Free Survival
Overall Survival
FOLFIRI vs mIFL: P = .004
FOLFIRI vs mIFL: P = .09
100
FOLFIRI vs Capelri: P = .015
100
FOLFIRI vs Capelri: P = .27
mIFL vs Capelri: P = .46
mIFL vs Capelri: P = .93 75 75
FOLFIRI
FOLFIRI
mIFL
mIFL
Progression Free (%) 50
Capelri
Alive (%) 50
Capelri
CapeIri, capecitabine, irinotecan; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; mIFL, modified irinotecan, bolus 5-fluorouracil, leucovorin.
The BICC‑C trial was designed to determine the therapeutic efficacy of bolus 5-FU plus irinotecan in metastatic colorectal cancer. The first phase of the BICC‑C trial, before antibodies were included in the regimens, showed a statistically significant improvement in progression-free survival for FOLFIRI with infusional 5-FU superior to bolus administration. Modified IFL is attractive because of its decreased toxicity, but few data exist on its use in this setting and therefore I do not suggest using this regimen. The CapeIri regimen was investigated as well but was associated with greater toxicity. Overall survival did not reach statistical significance, although this phase of the trial was ended early when bevacizumab was added to the regimen. 25 25 10 20 30 40 10 20 30 40 50
Months
Months
Fuchs CS, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30): Reprinted with permission from the American Society of Clinical Oncology.
Fuchs CS, et al. J Clin Oncol. 2007;25:

9. Access to Chemotherapy Improves Survival22
First-line therapy
Infusional 5-FU/LV + irinotecan 20
Infusional 5-FU/LV + oxaliplatin 18
Median OS (Mos)
Bolus 5-FU/LV + irinotecan 16
5-FU, 5-fluorouracil; LV, leucovorin; OS, overall survival.
This slide demonstrates Grothey’s hypothesis, also known as the 3-drug hypothesis. This graph shows what percentage of patients in various studies received all 3 drugs, including oxaliplatin, which was later approved by the FDA. These data suggest that treatment with all 3 drugs during the course of therapy extends median overall survival time. This was independent of whether first-line treatment was administered as a doublet or singlet. A caveat is that this is a retrospective analysis of many different studies and not a randomized trial.
Irinotecan + oxaliplatin 14
Bolus 5-FU/LV
LV5FU2 12 20 40 60 80
Patients With 3 Drugs (%)
Grothey A, et al. J Clin Oncol. 2005;23:

10. Efficacy: Sequence FOLFIRI/FOLFOX
Results
Arm A
Arm B
FOLFIRI  FOLFOX
FOLFOX  FOLFIRI
Patients, n
109 81
111 69
Confirmed RR, % 56 15 54 4
TTP, mos
8.5
4.2
8.0
2.5
Survival, mos
21.5
20.6
No statistically significant differences in first- or second-line therapy RR or TTP and OS
FOLFIRI, 5-fluorouracil/leucovorin/irinotecan; FOLFOX, 5-fluorouracil/leucovorin/oxaliplatin; OS, overall survival; RR, response rate; TTP, time to progression.
Tournigand and colleagues conducted a study that mandated the crossover from either FOLFIRI or FOLFOX at the time of progression. Results showed no significant difference in overall survival regardless of treatment arm. Therefore, clinicians must decide whether to use FOLFIRI or FOLFOX.
Tournigand C, et al. J Clin Oncol. 2004;22:

11. FOLFOXIRI vs FOLFIRI: Trial Design
FOLFOXIRI Irinotecan 165 mg/m2 Day 1 Oxaliplatin 85 mg/m2 Day 1 LV 200 mg/m2 over 2 hours Day 1 5-FU 3200 mg/m2 48-hour infusion Days 2, 3 Every 2 wks
(n = 122)
Patients with unresectable, previously untreated metastatic colorectal cancer
(N = 244)
FOLFIRI Irinotecan 180 mg/m2 Day 1 LV 100 mg/m2 over 2 hours Days 1, 2 5-FU 400 mg/m2 bolus, then 600 mg/m2 22-hour infusion Days 1, 2 Every 2 wks
(n = 122)
Primary endpoint: RR
Stratification: study center, PS (0/1-2), adjuvant chemotherapy
Falcone A, et al. ASCO Abstract 3513.

12. FOLFOXIRI vs FOLFIRI: Efficacy and Tolerability
FOLFOXIRI, % (n = 122)
FOLFIRI, % (n = 122)
P Value RR
Complete 7 6
< .0001*
Partial 53 28
Stable disease 21 34 --
Median PFS, mos
9.8
6.9
.0006
Median OS, mos
22.8
16.7
.032
Grade 3/4 toxicity
Neutropenia 50
.0008
Neurotoxicity† 20
< .0001
Diarrhea 12
.08
*External review; 95% CI for overall response: for FOLFIRI, for FOLFOXIRI. †Includes grade 2 events.
Falcone A, et al. ASCO Abstract 3513.

13. Quimioterapia más Bevacizumab

14. VEGF es expresado durante toda la historia natural
bFGF
TGFb-1
bFGF
TGFb-1
bFGF
TGFb-1
bFGF
VEGF
VEGF
VEGF
VEGF
VEGF
TGFb-1
PIGF
PIGF
PD-ECGF
PIGF
PD-ECGF
Pleiotrophin
Evolución tumoral
bFGF = basic fibroblast growth factor TGFb-1 = transforming growth factor b-1 PIGF = placenta growth factor PD-ECGF = platelet-derived endothelial cell growth factor
Adapted from Folkman. Cancer. Principles and practice of oncology 2005

15. Bevacizumab (Avastin®): Mecanismo de Acción
VEGF
KEY POINT: A number of environmental, hormonal, and genetic factors can lead to VEGF overexpression. P P P P

16. Bevacizumab (Avastin®): Mecanismo de Acción
VEGF
Bevacizumab
KEY POINT: A number of environmental, hormonal, and genetic factors can lead to VEGF overexpression. P P P P
BLOQUEO de la activación del VEGFR

17. Phase III Trial With Bevacizumab Therapy in First-Line MCRCD O M I Z E
Bolus IFL + placebo
(n = 412)
Untreated
MCRC
Bolus IFL + BV
(n = 403)
A study of 800 patients investigated the efficacy and safety of bevacizumab (BV) in combination with bolus IFL as first-line therapy for metastatic colorectal cancer. Patients were randomized to receive one of 3 treatment strategies: IFL plus placebo with no BV allowed, even after disease progression (n=412), IFL plus BV with optional BV after disease progression (n=403), or 5-FU/LV plus BV with optional BV after disease progression (n=110).
IFL treatment included bolus 5-FU (500 mg/m2), LV (20 mg/m2), and irinotecan (125 mg/m2) administered on weeks 4 and 6. 5-FU/LV treatment included bolus 5-FU (500 mg/m2) and LV (500 mg/m2) administered on week 6 and 8. BV (5 mg/kg) was administered every 2 weeks.
The primary endpoint for the study was duration of survival. Secondary endpoints included response rate (PR + CR), PFS, QOL, and safety.
5-FU/LV + BV
(n = 110):
Closed due to lack of efficacy
Hurwitz. NEJM, 2004
Courtesy of: Paulo Hoff
Hurwitz H, Fehrebacher L, Cartwright T, et al. Presented at the American Society of Clinical Oncology Annual Meeting. June 1, 2003, Chicago, Illinois.

18. Phase III Trial : PFS
Median PFS (months) IFL + placebo: 6.2 (95% CI: 5.6–7.7) IFL + bevacizumab: 10.6 (95% CI: 9.0–1.0) HR=0.54 (95% CI: 0.45–0.66) p<0.001
1.0
0.8
0.6
0.4
0.2
Probability of being progression-free
IFL + bevacizumab
IFL + placebo
Progression-free survival was also significantly increased by 71% in the IFL/bevacizumab arm (10.6 [95% CI 9.0–11.0] vs 6.2 [95% CI 5.6–7.7] months, p<0.001).
The stratified HR for disease progression or death during first‑line therapy in arm 2 relative to arm 1 was 0.54 (95% CI 0.45–0.66).
It is interesting to note that the difference in overall and progression-free survival between the two treatment arms is relatively constant at 4.7 and 4.4 months.
Together with the study design, in which the treatment arms differed only with the addition of bevacizumab to IFL and switching to alternative first-line therapies if toxicity occurred, this suggests that the increase in survival is due to the addition of bevacizumab.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colorectal cancer. N Engl J Med 2004;350:2335–42.
6.2
10.6
PFS (months)
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Courtesy of: Paulo Hoff

19. Phase III Trial: Survival
Median survival (months) IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs
IFL + bevacizumab: 20.3 (95% CI: 18.5–24.2)
HR=0.66 (95% CI: 0.54–0.81) p<0.001
1.0
0.8
0.6
0.4
0.2
IFL + bevacizumab
IFL + placebo
Probability of survival
Survival, the primary endpoint, was significantly increased by 30% in the IFL/bevacizumab arm compared with the IFL/placebo arm (20.3 [95% CI 18.5–24.2] vs 15.6 [95% CI 14.3–17.0] months, respectively; p<0.001).
The HR of death for arm 2 relative to arm 1 was estimated to be 0.66 (95% CI 0.54–0.81). This corresponds to an average reduction of 34% in the risk of death in the IFL/bevacizumab arm.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colorectal cancer. N Engl J Med 2004;350:2335–42.
15.6
20.3
Survival (months)
Hurwitz H et al. N Engl J Med 2004;350:2335–42
Courtesy of: Paulo Hoff

20. Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design
Initial design
Amended design
FOLFIRI (n=144)
FOLFIRI+Bev.
(n=60)
mIFL
(n=141)
mIFL+Bev. R R
(n=57)
n=430
n=117
XELIRI
(n=145)
May 2004 – Dec 2004
Feb 2003 – April 2004
Protocol amended due to approval of bevacizumab
Primary endpoint: PFS
* Celecoxib data not shown
Fuchs et al, JCO 2008
Courtesy of: Paulo Hoff

21. Proportion of Subjects Who Survived Survival Time (months)
Overall Survival
Regimen
Median OS (months)
1 Year
P Value
FOLFIRI+ BEV 28
87% --
mIFL + BEV
19.2
61%
0.01 1
0.9
0.8
0.7
0.6
Proportion of Subjects Who Survived
0.5
0.4
0.3
FOLFIRI + Bevacizumab
mIFL + Bevacizumab
0.2
0.1 10 20 30 40
Survival Time (months)
Fuchs et al. JCO 2008
Courtesy of: Paulo Hoff

22. Phase III Trial of Bevacizumab + Panitumumab-CT With Bev-CT in CRC (PACCE)
Hecht JR, et al. JCO 2008

23. Impact of bevacizumab on OS in mCRC: a population-based study
Patients with mCRC (n=1,417): 2003–2004 (pre-bevacizumab) versus 2006 (post-bevacizumab)
Proportion of patients receiving
Irinotecan or oxaliplatin and 5-FU: no change (p=0.68)
Anti-EGFR therapy: no change (p=0.63)
Bevacizumab therapy: increased 5.9% vs 30.6% (p<0.001)
Slide taken from Arnold presentation, GICEF 2009
Addition of bevacizumab to systemic chemotherapy significantly improved OS: 23.6 vs 18.6 months (p<0.001)
Renouf, et al. ASCO GI 2009

24. Impact of bevacizumab in mCRC: significantly improved OS
1.0
0.8
0.6
0.4
0.2
Bevacizumab era (2006) 30.6% received bevacizumab
Estimated probability
Pre-bevacizumab (2003–2004) 5.9% received bevacizumab
p<0.001
Bevacizumab + standard chemotherapy significantly improved OS: 23.6 vs 18.6 months (p<0.001) 6 12 18 24 30
OS (months)
Bevacizumab era (2006), n=448 Pre-bevacizumab (2003–2004), n=969
Renouf, et al. ASCO GI 2009

25. Phase IV BRiTE Therapy in First-Line MCRCO L
Untreated
MCRC
Bev + CT
Grothey, et al. JCO 2008
Hurwitz H, Fehrebacher L, Cartwright T, et al. Presented at the American Society of Clinical Oncology Annual Meeting. June 1, 2003, Chicago, Illinois.

26. Phase IV BRiTE Therapy in First-Line MCRCO L
PFS FOLFOX + Bev: 10 m (n=1092)
Untreated
MCRC
Bev + CT
PFS FOLFIRI + Bev: 10.4 m (n=280)
Grothey, et al. JCO 2008
Hurwitz H, Fehrebacher L, Cartwright T, et al. Presented at the American Society of Clinical Oncology Annual Meeting. June 1, 2003, Chicago, Illinois.

27. Estimated probability
BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death)
Post-progression therapy
1.0
0.8
0.6
0.4
0.2
Bevacizumab post-PD (n=642) No bevacizumab post-PD (n=531)
No treatment (n=253)
Estimated probability
Post-progression bevacizumab HR=0.48 (95% CI: 0.41–0.57)
p<0.001
12.6
19.9
31.8
OS (months)
Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008
*Non-randomised, observational trial 27 27

28. Quimioterapia más cetuximab

29. Phase III MRC COIN R A N D O M I Z E XELOX/OxMdG (n = 815) Untreated
MCRC
XELOX/OxMdG +
Cetuximab
(n = 815)
A study of 800 patients investigated the efficacy and safety of bevacizumab (BV) in combination with bolus IFL as first-line therapy for metastatic colorectal cancer. Patients were randomized to receive one of 3 treatment strategies: IFL plus placebo with no BV allowed, even after disease progression (n=412), IFL plus BV with optional BV after disease progression (n=403), or 5-FU/LV plus BV with optional BV after disease progression (n=110).
IFL treatment included bolus 5-FU (500 mg/m2), LV (20 mg/m2), and irinotecan (125 mg/m2) administered on weeks 4 and 6. 5-FU/LV treatment included bolus 5-FU (500 mg/m2) and LV (500 mg/m2) administered on week 6 and 8. BV (5 mg/kg) was administered every 2 weeks.
The primary endpoint for the study was duration of survival. Secondary endpoints included response rate (PR + CR), PFS, QOL, and safety.
XELOX/OxMdG +
Cetuximab
(n = 815)
Intermitent
ESMO, 2009
Hurwitz H, Fehrebacher L, Cartwright T, et al. Presented at the American Society of Clinical Oncology Annual Meeting. June 1, 2003, Chicago, Illinois.

30. HR point estimate = 1.038 95% CI 0.90–1.20 p=0.68
COIN: K-ras WT OS
Survival probability
Arm A (XELOX/FOLFOX)
Arm B (XELOX/FOLFOX + cetuximab)
1.00
0.75
0.50
0.25
Arm A
Arm B
Diff.
Median OS, months
17.9
17.0
–0.92
2-year survival, %
36.1
34.4
-1.66
HR point estimate = % CI 0.90–1.20 p=0.68 6 12 18 24 30 36 42
Time (months)
No. at risk Arm A Arm B
367
362
316
306
250
238
154
149 83 80 44 42 19 17 1 3
ITT analysis
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)

31. HR point estimate = 0.959 95% CI 0.84–1.09 p=0.60
COIN: K-ras WT PFS
Survival probability
Arm A (XELOX/FOLFOX)
Arm B (XELOX/FOLFOX + cetuximab)
1.00
0.75
0.50
0.25
Arm A
Arm B
Diff.
Median PFS, months
8.6
+0.07
HR point estimate = % CI 0.84–1.09 p=0.60 6 12 18 24 30 36 42
No. at risk Arm A Arm B
367
361
245
249 92
103 41 42 18 22 11 9 6 1
ITT analysis
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)

32. Cetuximab + Chemotherapy
COIN: No Significant Difference in OS, PFS Between Treatment Arms, Pt Subsets
Survival Outcome, Mos
Cetuximab + Chemotherapy
Chemotherapy
HR (95% CI)
P Value
Wild-type KRAS
Median OS
17.0
17.9
1.038 ( )
.68
Median PFS
8.6
0.959 ( )
.60
All wild-type patients
19.9
20.1
1.019 ( )
.86
9.2
8.8
0.922 ( )
.36
Patients with mutated KRAS, NRAS, or BRAF
12.7
14.4
1.004 ( )
.96
6.3
6.6
1.079 ( )
.33
Maughan TS, et al. ASCO Abstract 3502.

33. ITT Survival: WT K-Ras (n=729)
XELOX/OxMdG
XELOX/OxMdG +
Cetuximab HR
(p value) OS
(months)
17,9
17,0
1,038
(0,68)
2y OS (%)
36,1
34,4
PFS
8,6
0,95
(0,60)
ESMO, 2009

34. COIN: K-RAS and Response
All patients
K-ras WT
K-ras MT
FOLFOX/ XELOX (n=815)
Cetuximab + FOLFOX/ XELOX (n=815)
FOLFOX/ XELOX (n=367)
Cetuximab + FOLFOX/ XELOX (n=362)
FOLFOX/ XELOX (n=268)
Cetuximab + FOLFOX/ XELOX (n=297)
Best overall response (%) 51 53 57 64 46 43
Odds ratio
1.08 (p=0.428)
OR=1.35 (p=0.049)
OR=0.88 (p=0.449)
Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)

35. NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV 60 mg/m2, d1,2 Q2W)
mCRC R
Nordic FLOX + Cetuximab
Nordic FLOX stop & go + Cetuximab
Endpoint:
PFS
Randomized patients: 571
Tveit KM, ESMO 2010

36. NORDIC VII: Cetuximab in First Line mCRC
Nordic FLOX (FU 500 mg/m2 + LV 60 mg/m2, d1,2 Q2W)
mCRC R
Nordic FLOX + Cetuximab
Nordic FLOX stop & go + Cetuximab
Outcome
FLOX
F+Cet
Stop&Go-Cet
PFS
7.9
8.3
7.3 RR
41%
49%
47% OS
20.4
19.7
20.3
Endpoint:
PFS
Randomized patients: 571
Tveit KM, ESMO 2010

37. TRIALS IN mCRC 1st Line treatment K-Ras status WTPH
PFS OS
CRYSTAL 3
FOLFIRI
FOLFIRI+
CETUXIMAB P
FOLFIRI + CETUXIMAB
8.4
9.9
0.0017 20
23.5
0.0094
OPUS 2
FOLFOX
FOLFOX +
FOLFOX + CETUXIMAB
7.2
8.3
0.006
18.5
22.8
0.3854
COIN
XELOX/
XELOX/FOLFOX+CETUXIMAB
XELOX/FOLFOX + CETUXIMAB
8.6
0.6
17.9 17
0.68
NORDIC
FLOX
FLOX + CETUXIMAB
7.9
0.3
20.4
19.7
0.30

38. mCRC with progression after 1st line fluoropyirimidine and Oxaliplatin
EPIC: Cetuximab + Irinotecan after Fluoropyrimidine + Oxaliplatin failure
Cetuximab 400 mg/m2 initial dose cycle 1, wk 1, 250 mg/m2 weekly
Irinotecan 350 mg/m2
(n=648)
mCRC with progression after 1st line fluoropyirimidine and Oxaliplatin
(n=1298) R
Irinotecan
(n=650)
Primary endpoint:
Overall survival
Sobrero AF. J Clin Oncol. 26: , 2008

39. Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC
Cet + Iri
(n=648)
Iri
(n=650)
P value RR
16.4%
4.2%
P<0.05
PFS
4 months
2.6 months
P<0.005 OS
10.7 m
10 m
P=0.71
Sobrero AF. J Clin Oncol. 26: , 2008

40. Cetuximab versus BSC Cetuximab + BSCN D O M I Z E
Cetuximab
+ BSC
(287)
Metastatic colorectal cancer with prior 5-FU, irinotecan and oxaliplatin
(572 pts)
BSC
(285)
Jonker et al. NEJM 2007; 357: 2040
Courtesy of: Paulo Hoff
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23-30.

41. NCIC CTG C0.17: Overall Survival in K-ras Wild-Type Patients
0.2
0.4
0.6
0.8 1 2 4 6 8 10 12 14 16 18
Time from Randomization (Months)
Proportion Alive
Cetuximab
BSC
Study arm
MS (months)
95% CI
Cetuximab + BSC
9.5
7.7 – 10.3
BSC alone
4.8
4.2 – 5.5
HR % CI (0.41,0.74)
Log rank p-value: <0.0001
Cetuximab
BSC
117
108 95 81 52 34 20 9 6 2
113 92 69 36 24 17 12 5 3
Courtesy of: Paulo Hoff
Karapetis C et al, New Engl J Med 2008

42. Continuum of care 42

43. OPTIMOX2: Study Design OPTIMOX1 (n = 100) Until progression mFOLFOX7
6 cycles
s5-FU/LV2
mFOLFOX7
6 cycles
Patients with metastatic colorectal cancer
(N = 202)
OPTIMOX2 (n = 102)
mFOLFOX7
6 cycles
Chemotherapy- free interval*
mFOLFOX7
6 cycles
mFOLFOX7: oxaliplatin, 100 mg/m2 Day 1; leucovorin, 400 mg/m2 Day 1; 5-fluorouracil 48-hour continuous infusion, 3000 mg/m2 Days 1-2; every 2 wks
s5-FU/LV2: 5-fluorouracil 400 mg/m2 bolus Day 1, then 3000 mg/m2 48-hour continuous infusion Days 1-2; leucovorin, 400 mg/m2 Day 1; every 2 wks
Primary endpoint: duration of disease control (DDC)
*Median duration: 20 weeks
Started before tumor progression reached baseline measurements
Maindrault-Goebel F, et al. ASCO Abstract 3504.

44. OPTIMOX2: DDC and PFS
No difference observed in duration of disease control between study arms
Longer median PFS with OPTIMOX1 regimen
Results, mos
OPTIMOX1
OPTIMOX2
P Value
DDC
12.9
11.7
.41
Median PFS
8.7
6.9
.009
DDC, duration of disease control; PFS, progression-free survival
Maindrault-Goebel F, et al. ASCO Abstract 3504.

45. Alternating vs Continuous FOLFIRI
Continuous FOLFIRI Every 2 wks for 6 mos
(n = 168)
Patients with advanced colorectal cancer without prior chemotherapy in the advanced setting
(N = 331)
Alternating FOLFIRI Every 2 wks, 2 mos
(n = 163)
Alternating FOLFIRI Every 2 wks, 2 mos
OS, overall survival; PD, progressive disease
Alternating FOLFIRI; Irinotecan 180 mg/m2 Day 1, LV 100 mg/m2 over 2 hours Days 1, 2, 5-FU 400 mg/m2 bolus, then 600 mg/m2 22 hour infusion Days 1,2, every 2 wks, 2 mos on 2 mos off
Continuous FOLFIRI; Irinotecan 180 mg/m2 Day 1, LV 100 mg/m2 over 2 hours Days 1, 2, 5-FU 400 mg/m2 bolus, then 600 mg/m2 22 hour infusion Days 1,2, every 2 wks for 6 mos
No treatment
2 mos
Evaluation for PD 2 mos from randomization, then every 4 mos thereafter Primary endpoint: OS
Labianca R, et al. ASCO Abstract 3505.

46. Alternating vs Continuous FOLFIRI in Advanced Colorectal Cancer (cont’d)
Alternating FOLFIRI not inferior to continuous FOLFIRI in terms of PFS and OS
Median follow-up: 30 months
Results, mos
A-FOLFIRI
C-FOLFIRI
HR (5% CI)
Median PFS
6.2
6.5
1.01 ( )
Median OS
16.9
17.6
1.03 ( )
A-FOLFIRI, alternating FOLFIRI; C-FOLFIRI, continuous FOLFIRI
Labianca R, et al. ASCO Abstract 3505.

47. MACRO: Maintenance Bev vs Continued Bev + XELOX in Patients With mCRC
XELOX + Bevacizumab
(n = 239)
Induction
Therapy
XELOX +
Bevacizumab
6 cycles
Patients with
previously
untreated mCRC
(N = 480)
Disease progression, severe toxicity, or consent withdrawal
Bevacizumab
(n = 241)
Maintenance cycles administered q3w:
Oxaliplatin 130 mg/m2 IV on Day 1
Capecitabine 1000 mg/m2 BID PO on Days 1-14
Bevacizumab 7.5 mg/kg IV on Day 1
Tabernero J, et al. ASCO Abstract 3501.

48. MACRO: Duration of PFS Comparable Between Bev vs XELOX + Bev
No significant difference between treatment arms in any efficacy outcome
Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be confirmed
The median PFS HR 95% CI ( ) beyond the planned noninferiority limit of 1.32
Outcome
Bevacizumab
(n = 241)
XELOX/ Bevacizumab
(n = 239) HR
(95% CI) OR
Median PFS,* mos
9.7
10.4
1.11
( ) --
Median OS,* mos
21.7
23.4
1.04
( )
Confirmed objective response, % 49 46
0.89
( )
*Median follow-up: mos.
Tabernero J, et al. ASCO Abstract 3501.

49. Estimated probability
BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death)
Post-progression therapy
1.0
0.8
0.6
0.4
0.2
Bevacizumab post-PD (n=642) No bevacizumab post-PD (n=531)
No treatment (n=253)
Estimated probability
Post-progression bevacizumab HR=0.48 (95% CI: 0.41–0.57)
p<0.001
12.6
19.9
31.8
OS (months)
Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008
*Non-randomised, observational trial 49 49

50. Advanced/mCRC Patients Can Tolerate Intensive Therapy
Primera línea
Segunda línea
Tercera línea
FOLFOX ± bevacizumab
CapeOx ± bevacizumab
FOLFIRI + bevacizumab
FOLFIRI ± cetuximab*
5-FU/leucovorin + bevacizumab
FOLFOXIRI (2B)
FOLFIRI
Irinotecan
FOLFOX
CapeOx
Irinotecan + cetuximab*†
Irinotecan → Irinotecan + cetuximab*†
Clinical trial
BSC
BSC, best supportive care; CapeOx, capecitabine/oxaliplatin; FOLFIRI, 5-fluorouracil/leucovorin/irinotecan; FOLFOX, 5-fluorouracil/leucovorin/oxaliplatin; FOLFOXIRI, 5-fluorouracil/leucovorin/oxaliplatin/irinotecan; 5-FU, 5-fluorouracil.
The complexity of the 2010 National Comprehensive Cancer Network (NCCN) guidelines reflects the complexity of the decision you just made. Several options are available, including FOLFOX or FOLFIRI as the backbone with bevacizumab or cetuximab, CapeOX as a backbone, or 5-fluorouracil/leucovorin with bevacizumab. The NCCN would also allow for FOLFOX plus irinotecan (FOLFOXIRI), a multidrug combination therapy that has been tested in a few small studies. Second-line and third-line options include cetuximab with irinotecan or oxaliplatin-based therapies.
The NCCN guidelines note that panitumumab should not be used in combination whereas cetuximab can be used in combination. Recent data also support the use of panitumumab in combination regimens. The asterisks  on this slide highlight an important development: Only patients with wild-type KRAS should be treated with anti-EGFR antibodies (cetuximab or panitumumab).
*KRAS no mutado.
NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V

51. Irinotecán + Cetuximab
“Continuum of care”
1o línea
6 meses
Hasta progresión
FOLFOX + Bevacizumab
Bevacizumab
Tabernero J, et al. ASCO Abstract 3501.
2o línea
6 meses
Hasta progresión
FOLFIRI + Bevacizumab
Fluoruracilo
Grothey A, et al. JCO Nov 20, 2008:
≥3o línea
Hasta progresión
Hasta progresión
Irinotecán + Cetuximab
Mitomicina-FU
Cunningham D, et al. N Engl J Med 2004;351:

52. Conclusiones FU / Iri / Ox en algún momento de la enfermedad
Bevacizumab + QT en primera línea metastásica
Cetuximab +/- Irinotecán en última línea
Disminución de intensidad (y toxicidad) es válida (sábados)
Suspender el tratamiento: disminuye la supervivencia (domingos)