Therapeutic Strategies in Adjuvant Therapy of Colon Cancer

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 93.2IIa 100 91.0 84.7IIb 100 80.2 72.2IIIa 100 91.4 83.4IIIb 100 77.3 64.1IIIc 100 67.1 52.3IIId 100 57.3 43.0IIIe 100 43.1 26.8IV 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 60.85-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

Estim

ated

pro

babi

lity

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

Estim

ated

pro

babi

lity

Test of non-inferiority p=0.000116Test of superiority p=0.06

5-year OS (%)Capecitabine 1, 004 71.45-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/

vomiting

Stomatitis

Diarrhoea

Febrile

neutropenia HFS

Patie

nts

(%)

* * * *

*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

Estim

ated

pro

babi

lity

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)

Estim

ated

pro

babi

lity

1.0

0.8

0.6

0.4

Years0 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

Patie

nts

(%)

CAPOX1 (n=938) FOLFOX42 (n=1,108)FLOX3 (n=1,200)

Cross-trial comparison*Not reported

Neutropenia

Nausea

Stomatitis

Diarrhoea

Febrile

neutropenia HFS

Vomiting

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.

DFS

(%)

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, 20043300 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 ValueMMR (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 ValueBoth 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.