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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. - PowerPoint PPT Presentation
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Therapeutic Strategies in Adjuvant Therapy of Colon CancerMohamed 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 epitheliumDysplastic aberrant crypt fociInitial adenoma developsIntermediate adenomaLate adenomaCarcinomaMetastasisMutation in APCMutation in K-rasMutation in DCCMutation in p53Other alteration?EGFR & VEGF
Who Should Receive Adjuvant Therapy?1. Staging System:OConnellJB, 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-StageN-StageV1 (micro).V2 (macro)
Isolated Tumor Cells & Micrometastases0 0.2 mm (N0)0.2 2 mm (N1mi)
Stage III Not IVCancer 2008;112:504.
Who Should Receive Adjuvant Therapy?3. Peri-neural Invasion:An Under-Estimated Variable:15 25%JCO.2009.22.4949
1/5 : Peritoneal Minimal Residual Disease.1/7 : Peritoneal Carcinomatois.Who Should Receive Adjuvant Therapy?3. Peritoneal Minimal Residual Disease: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 CancerLower Toxicity Profile & Better ComplianceNSABP Co1-6IMPACTNCCTGNCIC-CTG30%
Chemotherapeutics Other Than Fluoropyremidines:Stage III Colon Cancer:OxaliplatinUFTCapecitabineIrinotecanEffectiveness.Comparable Toxicity Profiles
Adjuvant FOLFOX4 in Stage II-III Colon Cancer: MOSAIC Study Schemade 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 (contd)Rate of peripheral sensory neuropathy decreased over timeAt 4 yrsGrade 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 LV5FU2Febrile neutropenia in 1.8% of patients receiving FOLFOX4de Gramont A, et al. ASCO 2007. Abstract 4007.
No Significant Survival Advantage for The Following Groups: Stage II Disease.Stage III Disease:Female Sex.> 65 Years old.T4 Tumors.N1 Disease.Poorly Differentiated Tumors.CEA > 5.Vascular Invasion.
Final MOSAIC Results (contd)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.2009,27:3117-3125After Exclusion of Cases Developed Second Primary in Both Arms
Equivalent PFS in Head to Head Comparison in Metastatic Sitting.
Biological Alteration in Metastatic or Recurrent Disease (Topoisomerase I).Oxaliplatin Versus Irinotecan:J Clin Oncol.2005, 23:4866-4875
IntestineLiverCapecitabine5'-DFCR5'-DFURCyD5'-DFCR5'-DFUR5-FUTumor >> healthy tissueCapecitabineCyDCE5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine;CyD = cytidine deaminase; CE = carboxylesteraseCapecitabine mode of action:TP-activation proof of concept at last?Thymidinephosphorylase (TP)
X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancerPrimary endpoint: non-inferiority in DFSSecondary endpoint: OSBolus 5-FU/LV5-FU 425mg/m2 + LV 20mg/m2 days 15 q4wCapecitabine1,250mg/m2 b.i.d. days 114 q3w Chemonave stage III resection 8 weeks n=1, 004 n=983R A N D O M I SA T I O NData cut-off: January 2007b.i.d. = twice dailyTwelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
X-ACT: 5-year OS (median follow-up 6.8 years)HR=0.86 (95% CI: 0.741.01)NI margin 1.14064248789612182430365460667284901021.00.80.60.40.20Estimated probabilityTest of non-inferiority p=0.000116Test of superiority p=0.065-year OS (%)Capecitabine 1, 004 71.45-FU/LV983 68.4n0642487896Months1218243036546066728490102Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)
X-ACT and MOSAIC: projection of OS in stage III patientsITT populationEstimated probability024681.00.80.60.4YearsX-ACT1MOSAIC21Twelves 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)Estimated probability1.00.80.60.4Years02468
Chemo/ radiotherapy-nave stage III colon cancer Bolus 5-FU/LV Mayo Clinic or Roswell ParkCAPOXCapecitabine 1,000mg/m2 b.i.d. days 115 Oxaliplatin 130mg/m2 day 1 q3wSchmoll HJ, et al. J Clin Oncol 2007;25:421723CAPOX: a new optionin the adjuvant setting:Primary endpoint: disease-free survivaln=944 n=942R A N D O M I SA T I O N
Grade 3/4 adverse eventsPatients (%)CAPOX1 (n=938) FOLFOX42 (n=1,108)FLOX3 (n=1,200)Cross-trial comparison*Not reportedNeutropeniaNauseaStomatitisDiarrhoeaFebrile neutropeniaHFSVomitingNeurosensory1Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034) 2Andr T, et al. N Engl J Med 2004;350:234351 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:**50403020100
Newly Emerged Strategies:Stage III Colon Cancer:NSABP-C0 - 6: 1608 ptsUFT5-Fu/LVDFSOAS66.9%68.3%78.7%78.7%Similar Toxicity Profile
Targeted Therapy in The Adjuvant Sitting
Stages at which angiogenesis plays a role in tumor progressionPremalignant stageMalignant tumorTumor growthVascular invasionDormant micrometastasisOvert metastasisAvascular tumorAngiogenic switchVascularized tumorTumor cell intravasationSeeding in distant organsSecondary angiogenesisAngiogenesis Is Involved Throughout Tumor Growth and MetastasisPoon 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 trials20042005200620072008200920102011XELOXA final safetyXELOXA 1 efficacyXELOXA survival follow-upQUASAR-2 1 efficacyAVANT 1 efficacyNSABP C-08 1 efficacy
NSABP Protocol C-08: mFOLFOX Bevacizumab in Stage II/III CRCWolmark 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 postoperativelymFOLFOX6 regimen: LV 400 mg/m2 IV, 5-FU 400 mg/m2 IV, 5-FU 2400 mg/m2 over 46 hours; oxaliplatin 85 mg/m2 IVPrimary endpoint: DFS
NSABP Protocol C-08: 3-Yr DFS Results:Wolmark N, et al. ASCO 2009. Abstract LBA4. DFS (%)Yrs02040608010000.51.01.52.02.53.03.5HR: 0.89 (P = .15)mFF6 + B mFF6Events 291 3123-Yr DFS 77.4 75.5
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 IIStage IIIStage IIStage IIIStage IIStage IIStage IIIStage IIStage IIStage 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 PTSSurgerySurgery +5-Fu/LV5% OAS1% Mortality5% OAS5% OAS1% Mortality5% OAS
Stage II Colon Cancer:Kerr D, et al. ASCO 2009. Abstract 4000.
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 intervalKerr D, et al. ASCO 2009. Abstract 4000.
Clinical or Pathologic VariableHR (95% CI)P ValueMMR (deficient vs proficient)0.32 (0.15-0.69)< .001Tumor stage (T4 vs T3)1.83 (1.23-2.75).005Tumor grade (high vs low)0.62 (0.40-0.96).026Number of nodes examined (< vs 12)1.47 (1.01-2.14).040LVI (present vs absent)1.40 (0.88-2.23).175Recurrence score (continuous, per 25 units)1.61 (1.13-2.29).008
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).
Prognostic Value of CRC Biomarkers: Translational Study on PETACC 3Roth AD, et al. ASCO 2009. Abstract 4002.
Translational Study on PETACC 3: Results:Strong effect in stage II, decreases in stage III diseaseRoth AD, et al. ASCO 2009. Abstract 4002.
Parameter, %HR95% CIP ValueBoth stage II and III (N = 1233) RFS0.5690.400-0.811.0018 OS0.5480.357-0.842.006Stage II (n = 391) RFS0.2650.107-0.661.0044 OS0.1590.039-0.659.011Stage III (n = 842) RFS0.6930.473-1.02.06 OS0.6990.446-1.09.12
Stage II Colon Cancer:Preoperative CEA Level:Journal of Surgical Oncology 2009;99:6570
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.