therapeutic strategies in adjuvant therapy of colon cancer mohamed abdulla (m.d.) prof. of clinical...
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Therapeutic Strategies in Adjuvant Therapy of Colon Cancer
Mohamed Abdulla (M.D.)Prof. of Clinical Oncology,Kasr El-Aini School of Medicine,Cairo University.
01/04/2010
Colon Cancer; Challenging Issues: Better Understanding of the Molecular
Events. Better Characterization of Prognostic
Groups. Diagnosis in Younger Age Groups with
Aggressive Behavior. Introduction of Pharmaceuticals Other
Than Fluoropyremidines. Introduction of Targeted Therapies.
The Adenoma-Carcinoma Process:
Kinzler KW, et al. New York, The genetic basis of human cancer. NY: McGraw-Hill, 1998:565-87. Vogelstein B, et al. N Engl J Med. 1988;319:525-532. Fearon ER, et al. Cell. 1990;61:759-767.
Normal colonic epithelium
Dysplastic aberrant crypt foci
Initial adenoma develops
Intermediate adenoma
Late adenoma
Carcinoma
Metastasis
Mutation in APC
Mutation in K-ras
Mutation in DCC
Mutation in p53
Other alteration?
EGFR & VEGF
Who Should Receive Adjuvant Therapy?1. Staging System:
Stage 0 month 30 m 60 m
% Survival % Survival % Survival
I 100 96.1 93.2
IIa 100 91.0 84.7
IIb 100 80.2 72.2
IIIa 100 91.4 83.4
IIIb 100 77.3 64.1
IIIc 100 67.1 52.3
IIId 100 57.3 43.0
IIIe 100 43.1 26.8
IV 100 17.3 8.1
O’ConnellJB, Maggard MA, Ko CY: Colon Cancer Survival Rates with The New American Joint Committee on Cancer, Sixth Edition Staging. J Natl Cancer Inst 2004;96:1423.
LNs = > 12
Who Should Receive Adjuvant Therapy?2. Mesentric Nodules: (Contour Role):
T-Stage N-Stage
1. V1 (micro).
2. V2 (macro)
Isolated Tumor Cells &
Micrometastases
0 – 0.2 mm (N0)
0.2 – 2 mm (N1mi)
Stage III Not IV
Cancer 2008;112:50–4.
Who Should Receive Adjuvant Therapy?3. Peri-neural Invasion:An Under-Estimated Variable:
15 – 25%
JCO.2009.22.4949
Who Should Receive Adjuvant Therapy?3. Peritoneal Minimal Residual Disease:
1/5 : Peritoneal Minimal Residual Disease.
1/7 : Peritoneal Carcinomatois.
Surgical Techniques. Intraperitoneal & Intraportal Chemotherapy. HIPEC. Prevention of The Inflammatory Response.
thelancet.com/oncology Vol 10 January 2009
Who Should Receive Adjuvant Therapy?4. Age Factor:
Bouvier et al, CANCER August 15, 2008 / Volume 113 / Number 4
Who Should Receive Adjuvant Therapy?5. Timing of Chemotherapy Initiation:
Hershman et al, CANCER December 1, 2006 / Volume 107 / Number 11
Accepted Standards of Care:Stage III Colon Cancer
Stage III Colon Cancer Patients
5-Fu/Leucovorin
Mayo Clinic Roswell Park De Gramont
Lower Toxicity Profile & Better
Compliance
NSABP
Co1-6
IMPACT
NCCTG
NCIC-CTG 30%
Chemotherapeutics Other Than Fluoropyremidines:Stage III Colon Cancer:
Oxaliplatin
UFT
Capecitabine
Irinotecan
Effectiveness.
Comparable Toxicity Profiles
Adjuvant FOLFOX4 in Stage II-III Colon Cancer: MOSAIC Study Schema
de Gramont A, et al. ASCO 2007. Abstract 4007.
FOLFOX4
Leucovorin 200 mg/m2 IV +5-FU 400 mg/m2 bolus +
5-FU 600 mg/m2 IV over 22 hrs +Oxaliplatin 85 mg/m2 IV
(n = 1123)
LV5FU2
Leucovorin 200 mg/m2 IV +5-FU 400 mg/m2 bolus +
5-FU 600 mg/m2 IV over 22 hrs(n = 1123)
Patients with previously untreated, completely resected
stage II-III colon cancer
(N = 2246)
MOSAIC Study: 6-Y OAS; by Treatment Arm:
J Clin Oncol. 2009,27:3109-3116
MOSAIC Study: 6-Y OAS; by Treatment Arm & Stage:
J Clin Oncol. 2009,27:3109-3116
Final MOSAIC Results (cont’d)
Rate of peripheral sensory neuropathy decreased over time At 4 yrs
Grade 1: 12.0% Grade 2: 2.8% Grade 3: 0.7%
Neutropenia ≥ grade 3 in 41.0% of patients receiving FOLFOX4 vs 4.7% of patients receiving LV5FU2 Febrile neutropenia in 1.8% of patients receiving FOLFOX4
de Gramont A, et al. ASCO 2007. Abstract 4007.
No Significant Survival Advantage for The Following Groups:
Stage II Disease.
Stage III Disease:
1. Female Sex.
2. > 65 Years old.
3. T4 Tumors.
4. N1 Disease.
5. Poorly Differentiated Tumors.
6. CEA > 5.
7. Vascular Invasion.
Final MOSAIC Results (cont’d)
J Clin Oncol. 2009,27:3109-3116J Clin Oncol, Vol 27, No 19 (July 1), 2009: pp 3082-3084
Role of Irinotecan in Adjuvant Treatment of Stage III Colon Cancer PETACC-3 Study:
J Clin Oncol.2009,27:3117-3125
Role of Irinotecan in Adjuvant Treatment of Stage III Colon Cancer PETACC-3 Study:
J Clin Oncol.2009,27:3117-3125
Role of Irinotecan in Adjuvant Treatment of Stage III Colon Cancer PETACC-3 Study:
J Clin Oncol.2009,27:3117-3125
After Exclusion of Cases Developed Second Primary in Both Arms
Oxaliplatin Versus Irinotecan:
Equivalent PFS in Head to Head Comparison in Metastatic Sitting.
Biological Alteration in Metastatic or Recurrent Disease (Topoisomerase I).
J Clin Oncol.2005, 23:4866-4875
IntestineLiver
Capecitabine
5'-DFCR
5'-DFUR
CyD
5'-DFCR
5'-DFUR
5-FU
Tumor >> healthy tissueCapecitabine
CyD
CE
5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine;CyD = cytidine deaminase; CE = carboxylesterase
Capecitabine mode of action:TP-activation – proof of concept at last?
Thymidinephosphorylase (TP)
X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancer
Primary endpoint: non-inferiority in DFS
Secondary endpoint: OS
Bolus 5-FU/LV5-FU 425mg/m2 +
LV 20mg/m2 days 1–5 q4w
Capecitabine1,250mg/m2 b.i.d. days 1–14 q3w
Chemonaïve stage IIIresection 8 weeks
n=1, 004
n=983
RANDO MISATION
Data cut-off: January 2007b.i.d. = twice daily
Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancer
Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
5-year DFS (%)
Capecitabine 1, 004 60.8
5-FU/LV 983 56.7
1.0
0.8
0.6
0.4
0.2
0
0 6 42 48 78 96
Months
HR=0.88 (95% CI: 0.77–1.01)NI margin 1.20
12 18 24 30 36 54 60 66 72 84 90
ITT population
Es
tim
ate
d p
rob
ab
ilit
y
102
n
Test of non-inferiority p<0.0001Test of superiority p=0.0682
X-ACT: 5-year OS (median follow-up 6.8 years)
HR=0.86 (95% CI: 0.74–1.01)NI margin 1.14
0 6 42 48 78 9612 18 24 30 36 54 60 66 72 84 90 102
1.0
0.8
0.6
0.4
0.2
0
Est
imat
ed p
rob
abili
ty
Test of non-inferiority p=0.000116Test of superiority p=0.06
5-year OS (%)
Capecitabine 1, 004 71.4
5-FU/LV 983 68.4
n
0 6 42 48 78 96
Months
12 18 24 30 36 54 60 66 72 84 90 102
Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
Neutropenia
Nausea/
vomiti
ng
Stom
atitis
Diarrhoea
Febrile
neutropenia HFS
Pat
ien
ts (
%)
**
* *
*p<0.001HFS = hand foot syndrome
Capecitabine (n=993)
5-FU/LV (n=974)
Grade 3/4 adverse events50
40
30
20
10
0
X-ACT: 5-year OS (median follow-up 6.8 years)
Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
X-ACT and MOSAIC: projection of OS in stage III patients
ITT population
Es
tim
ate
d p
rob
ab
ilit
y
0 2 4 6 8
1.0
0.8
0.6
0.4
Years
X-ACT1
Bolus 5-FU/LV (n=983)
Capecitabine (n=1,004)
MOSAIC2
LV5FU2 (n=675)
FOLFOX (n=672)
1Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)2De Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007)
Es
tim
ate
d p
rob
ab
ilit
y
1.0
0.8
0.6
0.4
Years
0 2 4 6 8
Chemo/radiotherapy-naïve stage III colon cancer
Bolus 5-FU/LVMayo Clinic or Roswell Park
CAPOXCapecitabine 1,000mg/m2 b.i.d. days 1–15 Oxaliplatin 130mg/m2 day 1 q3w
Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23
CAPOX: a new optionin the adjuvant setting:
Primary endpoint: disease-free survival
n=944
n=942
RANDO MISATION
Grade 3/4 adverse events
Pat
ien
ts (
%)
CAPOX1 (n=938)
FOLFOX42 (n=1,108)
FLOX3 (n=1,200)
Cross-trial comparison*Not reported
Neutropenia
Nausea
Stom
atitis
Diarrhoea
Febrile
neutropenia HFS
Vomiti
ng
Neurosensory
1Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034)2André T, et al. N Engl J Med 2004;350:2343–51
3Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500)
*
Adjuvant CAPOX: favourable toxicity compared with FOLFOX and FLOX:
* *
50
40
30
20
10
0
Newly Emerged Strategies:Stage III Colon Cancer:NSABP-C0 - 6: 1608 pts
UFT 5-Fu/LV
DFS
OAS
66.9% 68.3%
78.7%78.7%
Similar Toxicity Profile
Targeted Therapy in The Adjuvant Sitting
EGFR
HER2
HER3
HER4
Stages at which angiogenesis plays a role in tumor progression
Premalignantstage
Malignanttumor
Tumorgrowth
Vascularinvasion
Dormantmicrometastasis
Overtmetastasis
Avasculartumor
Angiogenicswitch
Vascularizedtumor
Tumor cellintravasation
Seeding indistant organs
Secondaryangiogenesis
Angiogenesis Is Involved Throughout Tumor Growth and Metastasis
Poon RT, et al. J Clin Oncol. 2001;19:1207-1225. Reproduced with permission from the American Society of Clinical Oncology.
Trials of bevacizumab/capecitabine/Oxaliplatin in the adjuvant setting
Trial n Cancer Treatment
E5202 (Cooperative)
3,610 Stage II colon FOLFOX ± bevacizumab (high risk) Observation (low risk)
NSABP C-08 (Cooperative)
2,714 Stage II/III colon FOLFOX ± bevacizumab
QUASAR-2 (Cooperative)
2,240 Stage II/III colon Capecitabine ± bevacizumab
XELOXA (Cooperative)
1,886 Stage III colon CAPOX vs bolus 5-FU (Mayo Clinic or Roswell Park regimen)
AVANT (Roche)
3,450 Stage II/III colon FOLFOX vs FOLFOX + bevacizumab vs XELOX + bevacizumab
Important adjuvant capecitabine/bevacizumab-based combination trials
2004 2005 2006 2007 2008 2009 2010 2011
XELOXA final safety
XELOXA 1° efficacy
XELOXA survival follow-up
QUASAR-2 1° efficacy
AVANT 1° efficacy
NSABP C-08 1° efficacy
NSABP Protocol C-08: mFOLFOX ± Bevacizumab in Stage II/III CRC
Wolmark N, et al. ASCO 2009. Abstract LBA4.
Arm A: mFOLFOX6 Q2W x 26 (n = 1356)
Arm B: mFOLFOX6 + Bevacizumab 5 mg/kg Q2W x 26
(n = 1354)
Pts with stage II or III colon adenocarcinoma with ECOG PS of 0/11
(N = 2710)
Pts stratified by number of positive lymph nodes and randomized between Days 29 and 50 postoperatively
mFOLFOX6 regimen: LV 400 mg/m2 IV, 5-FU 400 mg/m2 IV, 5-FU 2400 mg/m2 over 46 hours; oxaliplatin 85 mg/m2 IV
Primary endpoint: DFS
NSABP Protocol C-08: 3-Yr DFS Results:
Wolmark N, et al. ASCO 2009. Abstract LBA4.
DF
S (
%)
Yrs
0
20
40
60
80
100
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
HR: 0.89 (P = .15)mFF6 + BmFF6
Events291312
3-Yr DFS77.475.5
Anti-EGFR in Adjuvant ttt of Stage III Colon Cancer:
Study Duration: 11/05 11/11. DFS, OAS & Safety. FOLFOX4+Cetuximab vs FOLFOX4. ??
Stage II Disease:
Stage II Stage IIIStage II Stage IIIStage IIStage II Stage IIIStage II
Stage II Stage III
Issues to Be Considered:
75 – 80% are cured with surgery alone. No current method to identify the subset
of patients at higher risk of recurrence. Minimal benefit of adding chemotherapy. The associated significant morbidity.
Stage II Colon Cancer:
QUASAR STUDY, 2004
3300 PTSSurgery
Surgery +5-Fu/LV
5% OAS
1% Mortality
5% OAS5% OAS
1% Mortality
5% OAS
Stage II Colon Cancer:NSABP
C 01, 02, 04, 06(1851 Pts)
5 Reference
Genes
7Recurrence
Genes
6Treatment Benefit
Genes
QUASAR Study(1436/3239 Pts)
Surgery Surgery + 5-Fu/LV
Kerr D, et al. ASCO 2009. Abstract 4000.
Clinical or Pathologic Variable HR (95% CI) P Value
MMR (deficient vs proficient) 0.32 (0.15-0.69) < .001
Tumor stage (T4 vs T3) 1.83 (1.23-2.75) .005
Tumor grade (high vs low) 0.62 (0.40-0.96) .026
Number of nodes examined (< vs ≥ 12) 1.47 (1.01-2.14) .040
LVI (present vs absent) 1.40 (0.88-2.23) .175
Recurrence score (continuous, per 25 units) 1.61 (1.13-2.29) .008
Stage II Colon Cancer:QUASAR Validation Results:
• Recurrence score (per 25 units) predictive of DFS and OS DFS HR: 1.42 (95% CI: 1.09-1.84; P = .010) OS HR: 1.33 (95% CI: 1.01-1.76; P = .041)• No significant differences in treatment score by treatment interaction in OS, DFS, or relapse-free interval
Kerr D, et al. ASCO 2009. Abstract 4000.
Prognostic Value of CRC Biomarkers: Translational Study on PETACC 3
Roth AD, et al. ASCO 2009. Abstract 4002.
Study designed to compare the incidence of molecular biomarkers in pts with stage II/III CRC in the PETACC 3 trial (N = 3278).
Frequency of MSI-H significantly higher in stage II (22%) vs stage III (12%) disease (P < .0001).
Higher frequency of MSI detected in N0 tumors compared with N1 or N2 (P < .0001).
Higher tumor stage correlated with increased frequency of MSI (T1/T2 vs T3 vs T4) (P = .037).
Translational Study on PETACC 3: Results:
Strong effect in stage II, decreases in stage III disease
Parameter, % HR 95% CI P Value
Both stage II and III (N = 1233)
RFS 0.569 0.400-0.811 .0018
OS 0.548 0.357-0.842 .006
Stage II (n = 391)
RFS 0.265 0.107-0.661 .0044
OS 0.159 0.039-0.659 .011
Stage III (n = 842)
RFS 0.693 0.473-1.02 .06
OS 0.699 0.446-1.09 .12
Roth AD, et al. ASCO 2009. Abstract 4002.
Stage II Colon Cancer:Preoperative CEA Level:
Journal of Surgical Oncology 2009;99:65–70
Keep in Mind:
Number of LNs > 12. Timing: 4-8 wks. Age. Molecular Markers. 5-Fu/LV is the Backbone. Stage II Disease: Better Assessment. Stage III Disease: MOSAIC & X-ACT. The Role of Adjuvant Targeted Therapy.