1 / 45

ASCO 2010 Biomarker-driven Treatment in Stage II Colon Cancer: When to Hold and When to Fold

ASCO 2010 Biomarker-driven Treatment in Stage II Colon Cancer: When to Hold and When to Fold. Overview of adjuvant clinical trials in stage II colon cancer - results, challenges, and confusion. - Al B. Benson, III, MD

janna
Download Presentation

ASCO 2010 Biomarker-driven Treatment in Stage II Colon Cancer: When to Hold and When to Fold

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. ASCO 2010Biomarker-driven Treatment in Stage II Colon Cancer: When to Hold and When to Fold

  2. Overview of adjuvant clinical trials in stage II colon cancer - results, challenges, and confusion. -Al B. Benson, III, MD • Prognostic and predictive molecular biomarkers in stage II colon cancer current evidence and future perspective. -Sabine Tejpar, MD, PhD • Biomarker-driven treatment decisions in stage II colon cancer – making sense of what we know. -Neal J. Meropol, MD

  3. Overview of Adjuvant Clinical Trials in Stage II Colon Cancer - Results, Challenges, and Confusion Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University

  4. Trends in Oncology Care • Evidence-based practice/guidelines • Risk assessment • Pathology • Markers • Comparative Effectiveness Research (CER)

  5. Archie Chocrane identified three concepts related to the evaluation of a medical technology – efficacy, effectiveness, and efficiency: • Efficacy is the extent to which an intervention does more good than harm under ideal circumstances (i.e., in circumstances designed to maximize the effect of the intervention and eliminate confounding factors). (“Can it work?”) • Effectiveness is the extent to which an intervention does more good than harm when provided to real-world patients by physicians practicing in ordinary clinical settings. (“Does it work in practice?”) • Efficiency measures the effect of an intervention in relation to the resources it consumes. (“Is it worth it?”)

  6. Comparative Effectiveness • Individual factors contribute to differences in clinical outcomes • Race or ethnic diversity • Co-morbidities • Drug-drug interactions • Tumor heterogeneity • Tumor genetics • Host genetics

  7. Recurrence Risk & Treatment Benefit Markers Currently Used for Stage II Colon Cancer • According to current guidelines*: • Unlike in breast cancer, there are no molecular markers established in clinical practice for stage II colon cancer • No markers in stage II colon cancer identify patients with disproportionately high or low benefit from chemotherapy * NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009 ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004. Recurrence Risk Bowel obstruction or perforation T-Stage # of nodes assessed Tumor grade Lymphatic/vascular invasion Margin status Treatment Benefit None

  8. Colon Cancer: Expanded Changes in AJCC Substaging for Stage II and III Based on Expanded SEER Data (con’t) AJCC 7th edition

  9. Colon Cancer: Expanded Changes in AJCC Substaging for Stage II and III Based on Expanded SEER Data (con’t) AJCC 7th edition

  10. Observed survival rates for 28,491 cases with adenocarcinoma of the colon AJCC 7th edition

  11. Prognostic Factors in Colorectal Cancer COLLEGE OF AMERICAN PATHOLOGISTS CONSENSUS • Category I • path-local extent of tumor = pT • path-nodes = pN • blood or lymphatic invasion • post-op residual tumor = R (e.g., + margin) • post-op  CEA • Category IIA • tumor grade • radial margin status • residual tumor s/p neoadjuvant tx

  12. Estimates of 5 Year DFS (%) with Surgery Plus Adjuvant Therapy Nodal T stage Low Grade High Grade Status S+AT S+AT 0 nodes T3 73776570 T4 606651 57 T1-T2 62755368 1-4 nodes T3 49653856 T4 33512340 T1-T2 39572846 > 5 nodes T3 24431532 T4 1127 517 Adapted from Cill et al.. J Clin Oncol 22 :1801, 2004

  13. Existing Tools for Selecting Stage II Patients for Treatment Are Inadequate • Guidelines: presence of any existing risk marker categorizes patients into “higher risk” vs “standard risk” groups • No further discrimination for “standard risk” (the majority) • Not individualized or quantitative • In the absence of established predictive markers, treatment decisions today are based on the expectation that higher risk stage II colon cancer patients derive larger absolute benefit with adjuvant chemotherapy NCCN Clinical Practice Guidelines for Oncology: Colon Cancer v3.2009 ASCO Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer, JCO, 2004.

  14. Clinical Background • The 5 year overall survival rate for patients with stage II colon cancer is between 75% and 80% • Defining a specific high risk group of patients with stage II disease that may benefit from adjuvant chemotherapy remains a challenge • Retrospective analysis of molecular prognostic factors suggest that there may be subsets of patients with stage II disease who are at  higher risk of recurrence • Prognostic markers to identify these patients have not been validated in prospective trials • Treatment options are evolving • Role of biologics in adjuvant therapy

  15. INT 0089 Stage II 5-yr OS Stage III 5-yr OS All Stages 5-yr OS LDLV 77% 63% 67% HDLV 75% 63% 66% LEV 77% 60% 63% LDLV/LEV 75% 65% 67% Proc ASCO 17:982, 1998

  16. Multivariate Analysis for LN Negative Patients: INT-0089 CSS= cause-specific survival

  17. Cohort Definition 3444 resected Stage II colon cancer patients “Usual” Risk Stage II 3151 T3N0 tumor No obstruction No perforation High Risk Stage II 293 T4N0 tumor Obstruction Perforation

  18. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) Investigators • GruppoInterdisciplinareValutazioneInterventiOncologia (GIVIO) • National Cancer Institute Canada Clinical Trials Group (NCIC-CTG) • FondationFrancaise de Cancerologie Digestive (FFCD) • North Central Cancer Treatment Group (NCCTG) • University of Siena

  19. Survival by Receipt of Chemotherapy IMPACT B2 vs. SEER-Medicare SEER-Medicare IMPACT

  20. Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU based Chemotherapy in Adjuvant Colon Cancer DJ Sargent, S Marsoni, SN Thibodeau, R Labianca, SR Hamilton, V Torri, G Monges, C Ribic, A Grothey, S Gallinger ASCO 2008

  21. Pooled data (N=1027)

  22. DFS by MMR status, pooled data Treated (N=512) Untreated (N=515) 5 yr DFS 5 yr DFS dMMR 70% pMMR 67% HR: 0.79 (0.49-1.25) p=0.30 dMMR 80% pMMR 56% HR: 0.51 (0.29-0.89) p=0.009

  23. DFS in pMMR patients, Pooled data Stage II (N=428) Stage III (N=434) 5 yr DFS 5 yr DFS Untreated 41% Treated 58% HR: 0.64 (0.48-0.84) p=0.001 Untreated 72% Treated 77% HR: 0.84 (0.57-1.24) p=0.38

  24. QUASAR: 5FU/LV Chemotherapy Benefit in the 1,436 Evaluable Stage II Colon Cancer Patients RFI (recurrence-free interval) DFS (disease-free survival) OS (Overall Survival) Kerr et al., ASCO 2009, #4000

  25. QUASAR RESULTS: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon Cancer Multivariate Analysis

  26. Figueredo et al, JCO 22(16), 2004

  27. Approximate Number of Patients Needed to Detect a Realistic Treatment Benefit* • Dukes’ B Dukes’ C • No. of No. of • Survival ARR Patients Survival ARR Patients • At 3 years 85% 2.5% 8,000 65% 5.2% 3,400 • At 4 years 80% 3.3% 5,800 58% 6.0% 2,800 • At 5 years 75% 4.0% 4,700 50% 6.6% 2,400 • Abbreviation: ARR = absolute risk reduction • For 90% power of detecting the treatment benefit using two-tailed significance tests at the 5% level, • assuming the true relative risk reduction is 18% for both Dukes’ B and Dukes’ C. Buyse, Piedbois, 2001

  28. Recent Adjuvant Colon Cancer Trials • X-ACT • MOSAIC • NSABP C-07 • C89803 • PETACC 3 • ACCORD-02 • NSABP C-08 • N0147

  29. Disease-free Survival: Stage II and Stage III Patients 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR [95% CI] p-value Stage II 0.84 [0.62–1.14] 0.258 Stage III 0.78 [0.65–0.93] 0.005 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months p=0.258 3.8% p=0.005 7.5% Data cut-off: June 2006

  30. Disease-free Survival: High-risk Stage II Patients 1.0 0.9 0.8 7.2% 0.7 FOLFOX4 n=286 LV5FU2 n=290 0.6 0.5 Probability 3-year5-year FOLFOX4 85.4% 82.1% LV5FU2 80.4% 74.9% HR [95% CI]: 0.74 [0.52–1.06] High-risk stage II- defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion , <10 lymph nodes examined; Data cut-off: June 2006 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Disease-free survival (months) Exploratory analysis

  31. PETACC-3 (V307) LV5FU2 R A N D O M I Z AT I ON FA 200 mg/m2 F 5-FU bolus 400 mg/m2 5-FU CI 600 mg/m2 • Stratification: • Stage II vs. III • Center Day 1 Day 2 Repeat q 2 weeks for 12 Cycles Irinotecan 180 mg/m2 LV5FU2 as above IF Day 1 Day 2 VanCutsem PASCO 2005 abstract #8

  32. Efficacy Data for Treated Patients Randomly Assigned to the LV5FU2 Regimen Journal of Clinical Oncology, Vol 27, No 19 (July 1), 2009: pp. 3117-3125

  33. Fig 1. National Surgical Adjuvant Breast and Bowel Project Protocol C-07 Consolidated Standards of Reporting Trials diagram Kuebler, J. P. et al. J ClinOncol; 25:2198-2204 2007

  34. Fig 3. Treatment hazard ratio and 95% CI for disease-free survival according to patient subsets defined by baseline prognostic factors significant in multivariate analysis Kuebler, J. P. et al. J ClinOncol; 25:2198-2204 2007

  35. Fig 2. Kaplan-Meier estimates of disease-free survival by treatment Kuebler, J. P. et al. J ClinOncol; 25:2198-2204 2007

  36. NSABP C-08 Stage ll + lll Strat: # Pos. N Randomize mFF6 mFF6 + B

  37. NSABP C-08 DFS % Ev 3yDFS mFF6+B291 77.4 mFF6 312 75.5 HR 0.89 P 0.15 Yrs

  38. NSABP C-08 HR 0.08 0.05 0.02 0.004 0.0004

  39. DFS Stage III DFS Stage II Ev 3yDFS mFF6+B 40 87.4 mFF6 47 84.7 Ev 3yDFS mFF6+B 251 74.2 mFF6 265 72.4 Δ 1.8 HR 0.90 P 0.25 HR 0.82 P 0.35 Δ 2.7 NSABP C-08

  40. AVANT BO17920 Stage ll + lll Strat: # Pos. N 12 ’04- 5 ‘07 N=3450 Randomize FF4 + B Xelox + B FF4

  41. Low-Risk Patients MSS or MSI-L with retention of 18q alleles MSI-H Arm A: mFOLFOX6 q2w × 12 Arm B: mFOLFOX6 + bevacizumab* q2w × 12 Arm C: Observation only High-Risk Patients MSS/18q LOH or MSI-L/18q LOH are RANDOMIZED Stratify: Disease stage (IIA or IIB) Microsatellite stability (stable vs MSI) 18q LOH E5202 Trial Schema MSI-L = low-level microsatellite instability MSI-H = high-level microsatellite instability *Bevacizumab continued for an additional 6 months

More Related