G. Pentheroudakis - Colorectal cancer - State of the art
Trips of Erodotus, 600 BCColorectal Cancer: State of the Art G PentheroudakisAssistant Professor of Oncology Ioannina University Hospital
Advanced Colorectal Cancer 1. Most active combinations2. Incorporation of targeted agents and use of biomarkers 3. How to devise a rational treatment strategy
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
Signal transduction via KRAS Normano N, Tejpar S, Van Cutsem E, Ciardiello F. Nature Reviews Oncology 2009
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)
COIN: Results in patients with KRAS wt CRC Arm B Arm A OxMdG/XELOX OxMdG/XELOX + ERBITUX (n=367) (n=362) p-valueMedian OS, months 17.9 17.0 0.68Median PFS, months 8.6 8.6 0.6ORR at 12 weeks, % 50 59 0.015 Maughan T, et al. ECCO-ESMO 2009 (Abstract No. 6LBA)
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
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 estimatePFS 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
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
Adjuvant therapy1. Optimal adjuvant chemotherapy regimens 2. To treat or not to treat stage II CRC? 3. Incorporation of targeted agents in the adjuvant setting
2004 – 2005 THE MOSAIC STUDYN=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
OS Updated André T, et al. J Clin Oncol 2009;27:3109-16.
X-ACT STUDY Dukes’ C colon Capecitabine 1250 mg/m2 bid, d1–14, q21d n = 1004Randomize 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
IS ADJUVANT TREATMENT INDICATED IN STAGE II COLON CANCER ?Ioannina: Promenade in theOld Town
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.
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
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?
Goldberg RM et al.Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) inpatients (pts) with resected stage III colon cancer (CC):NCCTG Intergroup phase III trial N0147
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 mFOLFOX6Outcome (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 .133-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
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.