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Slide 1 of 50 Case Study • 62-year-old woman presents with intermittent bright red blood per rectum for the past 3 weeks. Sought attention from PCP • Medical history – Type 2 diabetes mellitus for 20 years – Obesity (BMI: 32) • Lifestyle issues – Exercises <30 minutes per week – Diet with 4–5 servings of red meat per week Slide 2 of 50 Risk Factors for Developing Colorectal Cancer Decreases Risk Increases Risk Uncertain Impact Screening Family history Statins Exercise Calcium/ vitamin D Aspirin IBD Diabetes Fiber Glycemic index Obesity Red meat Western diet Alcohol Smoking Fruits/vegetables Postmenopausal estrogen Folic acid IBD = irritable bowel disease. Courtesy of Jeffrey A. Meyerhardt, MD, MPH. Slide 3 of 50 Case Continues • CT of chest, abdomen, and pelvis shows no metastases • Colonoscopy reveals a sigmoid colon cancer • Patient undergoes a laparoscopic-assisted sigmoid colectomy. Pathology report: – 4.5-cm poorly differentiated adenocarcinoma – Penetrates to subserosa – 2 of 16 lymph nodes positive – T3 N1 M0 (stage IIIB) Slide 5 of 50 Question 1 What would you recommend for adjuvant therapy in this patient? a) 5-FU/leucovorin/oxaliplatin (FOLFOX) b) Capecitabine c) Intravenous 5-FU/leucovorin d) FOLFOX + bevacizumab e) FOLFOX + cetuximab Slide 6 of 50 Rationale for Adjuvant Treatment of Stage III Colon Cancer Surgery Alone Surgery + Adjuvant Chemotherapy Reprinted from Greene FL, et al. Ann Surg. 2002;236:416, with permission from Lippincott Williams & Wilkins. Slide 7 of 50 Adjuvant Capecitabine X-ACT Trial Stage III colon cancer N = 1987 Primary endpoint: equivalence in diseasefree survival (DFS) R A N D O M I Z E Capecitabine 1250 mg/m BID days 1–14, q3wk 24 weeks Mayo Clinic regimen IV 5-FU/LV 6 cycles 5-FU/LV Capecitabine Overall DFS (5 y) 57% 61% .07 Overall survival (5 y) 68% 71% .06 Courtesy of Christopher Twelves, MD. P Value Slide 8 of 50 MOSAIC Adjuvant Oxaliplatin Stage II (40%) and III (60%) colon cancer N = 2246 Primary endpoint: R A N D O M I Z E FOLFOX4 LV5FU2 Disease-free survival (DFS) FOLFOX4 Overall DFS (5 y) LV5FU2 P Value 73% 67% .003 Stage III 66% 59% .005 Stage II 84% 80% .26 79% 76% .06 Stage III 73% 69% .03 Stage II 87% 87% .99 Overall survival (6 y) Courtesy of Aimery de Gramont, MD. Slide 9 of 50 Targeted Biologic Treatments as Adjuvant Therapy • Currently no data regarding efficacy of bevacizumab, cetuximab, or panitumumab in adjuvant therapy • Bevacizumab trials – NSABP C-08 (stage II and III)—pending results – AVANT (stage II and III)—pending results – ECOG (stage II colon)—accruing • Cetuximab trials – NCCTG (stage III colon)—accruing – PETACC-8 (stage III colon)—accruing Slide 10 of 50 Clinical Challenges Associated with Treating this Patient • Diabetes mellitus – Predisposition for developing chemotherapy-induced neuropathy has been observed in patients whose nerves have been damaged by diabetes mellitus1 – 1 study showed higher risk of recurrence with diabetes mellitus2 • Obesity – Increased central adiposity prior to diagnosis of colorectal cancer associated with poorer overall and disease-specific survival3 – Do not dose cap 1.Quasthoff S, et al. J Neurol. 2002;249:9. 2. Meyerhardt JA, et al. J Clin Oncol. 2003;21:433. 3. Haydon AM, et al. Gut. 2006;55:62. Slide 11 of 50 Case Continues • The patient receives FOLFOX adjuvant therapy for 9 cycles but develops grade 2 persistent neuropathy • She continues adjuvant therapy with capecitabine for 2 additional months • Neuropathy diminishes to grade 1 after 6 months and is nearly resolved at 12 months after last dose of oxaliplatin Slide 12 of 50 Incidence of Neurosensory Symptoms During FOLFOX and Follow-up Incidence of Neurosensory Symptoms (%) Evaluable Patients n = 811 at 4 Years 60 Grade 1 Grade 2 Grade 3 50 40 Grade 0 84.3% Grade 1 12.0% Grade 2 2.8% Grade 3 0.7% 30 20 10 0 During Treatment 6 Months Courtesy of Aimery de Garamont, MD. 1 Year 2 Years 3 Years 4 Years Slide 13 of 50 Question 2 What other recommendations would you make after completion of adjuvant therapy? a) Surveillance with intermittent clinic visits, colonoscopies, and CT scans b) Increasing physical activity c) Avoidance of diet high in red meat, sugary desserts, and refined grains d) All of the above Slide 14 of 50 Recurrence, Hazard Ratio Exercise and Colon Cancer Recurrences 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 0.87 0.9 0.51 <3 3-8.9 9-17.9 18-26.9 0.55 >27 Meyerhardt et al Metabolic Equivalent Task [MET]-H/Wk of Physical Activity JAMA 2007 Meyerhardt JA, et al. J Clin Oncol. 2006;24:3535. Slide 15 of 50 Diet and Colon Cancer Recurrences Quintile of Western Pattern Diet 1 2 3 4 5 P Trend 0.95 1.51 1.75 3.28 <.0001 (0.66–1.36) (1.06–2.15) (1.19–2.58) (2.15–2.07) 0.98 1.51 1.64 3.25 (0.68–1.43) (1.05–2.17) (1.09–2.46) (2.04–5.19) Disease-free survival Energy-adjusted only Ref Multivariate adjusted Ref <.0001 Western pattern: high intakes of red meat, processed meat, refined grains, sweets and dessert, french fries, and high-fat dairy products Adapted from Meyerhardt JA, et al. JAMA. 2007;298:754-764, with permission from the American Medical Association. Slide 16 of 50 Case Continues • Patient increased her exercise level to walking 6 days per week for approximately 1 hour daily • A CT scan 3 months after therapy is read NED • The patient is followed every 3 months with clinic visits and carcinoembryonic antigen (CEA) testing • At 14 months, CEA rose from 2.0 to 7.4 Slide 17 of 50 Case Continues • CT of chest, abdomen, and pelvis shows 5 total lesions in her liver (bilobar); no lesions identified elsewhere • Patient’s neuropathy has fully resolved • She is evaluated by a liver surgeon who does not believe she is resectable at this point Slide 18 of 50 Question 3 What treatment would you offer the patient now? a) FOLFOX or FOLFIRI alone b) FOLFOX + bevacizumab c) FOLFIRI + bevacizumab d) FOLFIRI + cetuximab e) FOLFOX + bevacizumab + panitumumab f) Clinical trial Slide 19 of 50 FOLFOX 1st-Line Standard for Metastatic Colorectal Cancer NCCTG 9741 R A N D O M I Z E IFL (irinotecan/5-FU/LV) n = 264 FOLFOX (5-FU/LV/oxali) n = 267 IROX (irinotecan/oxaliplatin) n = 264 Response Rate (%) Time to Progress (Mo) Median Overall Survival (Mo) IFL 31 6.9 15.0 FOLFOX 45 8.7 IROX 35 6.5 Goldberg RM, et al. J Clin Oncol. 2004;22:23. Grade 3/4 Neutropenia (%) Grade 3/4 Diarrhea (%) Grade 3/4 Paresthesias (%) 40 28 3 19.5 50 12 18 17.4 36 24 7 Slide 20 of 50 Goldberg JCO 2004. Irinotecan vs Oxaliplatin–Phase II/III Data Reference Regimen N RR (%) TTP (Mo) OS (Mo) Tournigand1 FOLFIRI 109 56 8.5 21.5 FOLFOX 111 54 8.1 20.6 FOLFIRI 164 31 7 14 FOLFOX 172 34 7 15 IFL 147 33 8.9 17.6 FLOX 148 32 7.6 17.4 FOLFIRI 58 36 8.4 18.5 FOLFOX 58 40 9.8 20.8 Gruppo Oncologico Dell’Italia2 Hellenic Oncology Group3 CALGB 802034 1. Tournigand C, et al. J Clin Oncol. 2004;22:229. 2. Colucci G, et al. J Clin Oncol. 2005;23:4866. 3. Kalofonos HP, et al. Ann Oncol. 2005;16:869. 4. Venook A, et al. 42nd ASCO; June 2-6, 2006. Abstract 3509. Slide 21 of 50 Targeted Biologic Therapies in Metastatic Colorectal Cancer Targeted monoclonal antibodies represent some of the newest developments in colorectal cancer treatment • Bevacizumab: anti-VEGF • Cetuximab: EGFR inhibitor • Panitumumab: EGFR inhibitor Slide 22 of 50 Normal and Tumor Vasculature Normal Blood Vessels Maturation factors present Less dependent on cell survival factors ... .... . ....... Tumor Blood Vessels . ............ ... ... ......... ... ... .... . ............ .. Growth and survival factors (eg, VEGF) present .. ............ ... . ............ ... Less permeable Supporting pericytes present Leaky Fewer pericytes . ............ ... Reduced integrin expression Slide courtesy of A. Venook, MD. Illustration courtesy of Genentech BioOncology. Preferential expression of v3 v5 & 51 integrins Slide 23 of 50 Bevacizumab 3 Proposed Mechanisms of Action Early effect 1 Regression Later effect 3 Inhibition 2 Normalization Slide courtesy of A. Venook, MD. Illustration courtesy of Genentech BioOncology. Slide 24 of 50 Bevacizumab in Metastatic Colorectal Cancer Pivotal 1st-Line Trial R A N D O M I Z E IFL IFL + bevacizumab Bevacizumab + IFL (n = 402) IFL (n = 411) Hazard Ratio P Value Median OS (mo) 20.3 15.6 0.66 <.001 Median PFS (mo) 10.6 6.2 0.54 <.001 Response rate (%) 44.8 34.8 Median duration response (mo) 10.4 7.1 .004 0.62 Hurwitz H, et al. N Engl J Med. 2005;350:2335-2342. Copyright © 2005 Massachusetts Medical Society. All rights reserved. .001 Slide 25 of 50 Phase III Study of XELOX or FOLFOX4 ± Bevacizumab in 1st-Line MCRC Progression-Free Survival Estimate XELOX-1/NO16966 XELOX/FOLFOX4 + bevacizumab n = 699 (513 events) XELOX/FOLFOX4 + placebo 1.0 n = 701 (547 events) 0.8 HR = .83 [97.5% CI .72–.95] P = .0023 0.6 0.4 0.2 8.0 9.4 0 0 5 10 15 20 25 Months Courtesy of Leonard Saltz, MD. Slide 26 of 50 1st-Line Bevacizumab in Metastatic Colorectal Cancer Progression-Free Survival PFS or TTP (Months) Hurwitz1 12 Saltz2 (NO16966) 10.6 Fuchs3 (BICC-C) 11.2 9.4 10 8.0 8 8.3 7.6 6.2 5.9 6 4 2 0 L IF L IF m m LF FO + IR B B ev X O LF X O LF ev I+ I FO X/ IR LO ev FO X/ B LO + LF FO XE XE L IF L IF /B ev 1. Hurwitz H, et al. N Engl J Med. 2004;350:2335. 2. Saltz L, et al. 43rd ASCO; June 1-5, 2007. Abstract 4028. 3. Fuchs C, et al. 43rd ASCO; June 1-5, 2007. Abstract 4027. Slide 27 of 50 Bevacizumab Safety and Usage Guidelines • Cardiovascular events – Hypertension (60%–67%; severe, 7%–10%)1 ACE inhibitors, beta blockers, diuretics, calcium channel blockers Discontinue permanently for severe crisis Discontinue temporarily if severe hypertension uncontrolled with medications – Thromboembolic (TE) events (3.8%)2 Do not use if arterial TE <6 mo, or if active cardiovascular disease Give to >65 years of age (a relative risk) 1. Avastin (bevacizumab). Package insert. Genentech BioOncology; 2004. 2. Skillings J, et al. ASCO; May 13-17, 2005. Abstract 3019. Slide 28 of 50 Bevacizumab Safety and Usage Guidelines • Bleeding (grade 3/4 in 4% of patients with resected primary)1 – Avoid in patients with central nervous system metastases, lung metastases with central cavitation or hemoptysis, bleeding diathesis/coagulopathy – Safe in patients with primary colorectal cancer in place without active bleeding 1. Kopetz J, et al. GI ASCO; January 26-28, 2006. Abstract 243. Slide 29 of 50 Bevacizumab Safety and Usage Guidelines • Gastrointestinal (GI) perforations (1% with resected primary; 6% with unresected primary)1 – Careful use in patients with abdominal carcinomatosis, GI perforation/abdominal fistula/intra-abdominal abscess <6 mo – Use with caution in patients with acute diverticulitis, obstruction, history of abdominal/pelvic XRT – Wait >6–8 weeks after major surgery/invasive GI procedure before using • Surgical wound healing complications – Careful use in patients <28–56 days after surgery, nonhealing wound/ulcer/fracture, anticipated major surgery – Delay elective surgical procedures (hold bevacizumab >6 weeks preoperatively) 1. Kopetz J, et al. GI ASCO;January 26-28, 2006. Abstract 243. Slide 30 of 50 EGFR Activation Mediates Several Processes Available at http://commons.wikimedia.org/wiki/Image:EGFR_signaling_pathway.png Slide 31 of 50 1st-Line Cetuximab in Metastatic Colorectal Cancer CRYSTAL R A N D O M I Z E FOLFIRI n = 599 FOLFIRI + Cetuximab n = 599 FOLFIRI FOLFIRI + Cetuximab Hazard/ Odds Ratio Median PFS (mo) 8.0 8.9 0.85 1-year PFS (%) 23 34 Response rate (%) 39 47 % underwent surgery with curative intent 2.5 6 P Value .048 .004 3.0 .003 Van Cutsem E, et al. 43rd ASCO; June 1-5, 2007. Abstract 4000. Slide 32 of 50 Randomized, Open-Label, Controlled Phase IIIb Trial of Panitumumab in MCRC–PACCE Ox-CT (eg, FOLFOX) Investigator’s choice of oxaliplatinor irinotecanbased chemotherapy Iri-CT (eg, FOLFIRI) 1:1 R A N D O M I Z E 1:1 Panitumumab 6 mg/kg q2wk + ox-CT + bevacizumab n = 413 Ox-CT + bevacizumab n = 410 Panitumumab 6 mg/kg q2wk + iri-CT + bevacizumab n = 115 Iri-CT + bevacizumab n = 115 Stratification factors: ECOG score, prior adjuvant therapy, disease site, oxaliplatin doses/irinotecan regimen, number of metastatic organs Tumor assessments: q12wk until disease progression or intolerability Courtesy of Randy Hecht, MD. Slide 33 of 50 PACCE Trial of Panitumumab Efficacy by Central Review Bev + Ox-CT (n = 410) % Pmab+ Bev + Iri-CT (n = 115) % Bev + Iri-CT (n = 115) % 45 46 40 37 Complete response 0 <1 0 0 Partial response 45 45 40 37 29 34 26 36 9.5 m 11 m 10.6 m 10.7 m Best ORR Stable disease Median PFS Pmab+ Bev + Ox-CT (n = 413) % Pmab = panitumumab; Bev = bevacizumab; Ox-CT = oxaliplatin-based chemotherapy (eg, FOLFOX); IriCT = irinotecan-based chemotherapy (eg, FOLFIRI); ORR = overall response rate; PFS = progression-free survival. Courtesy of Randy Hecht, MD. Slide 34 of 50 Phase III Trial of Cetuximab, Bevacizumab, and FOLFOX/FOLFIRI CALGB/SWOG 80405 • 1st-line metastatic colorectal cancer • Planned accrual: 2289 R A N D O M I Z E FOLFOX or FOLFIRIa + bevacizumab FOLFOX or FOLFIRIa + cetuximab FOLFOX or FOLFIRIa + cetuximab + bevacizumab aPhysician-selected chemotherapy. Stratification based on chemotherapy, prior adjuvant chemotherapy, prior pelvic RT. US NIH Clinical Trials Database. http://www.clinicaltrials.gov/ct2/show/NCT00265850?term=80405&rank=1. Slide 35 of 50 EGFR Inhibitor–Induced Skin Reactions Acne-like rash Postinflammatory effects Dry skin Fissures Paronychia Pruritus 1 2 3 4 5 6 7 8 9 Description of severe cases THERAPY SUGGESTIONS Topical anti-acne creams (drying effect) +/- tetracyclines +/- antihistamines Slide courtesy of Eric Van Cutsem, MD, PhD. Pulse dye laser Emollients Hydrocolloid dressing Antiseptic soaks or Silver nitrate (pyogenic granuloma) Propylene glycol+/acetylsalicylate Case Continues • The patient enrolls in CALGB/SWOG 80405 • Her physician chooses FOLFOX, and she is randomized to bevacizumab-only arm – She tolerates it fairly well • Her initial scans show stable disease • After 7 months, her disease shows progression with increased liver metastases and several <1-cm lung nodules Slide 37 of 50 Question 4 What treatment would you offer the patient now? a) FOLFIRI + bevacizumab b) Irinotecan + cetuximab c) Irinotecan + cetuximab + bevacizumab d) Clinical trial Slide 38 of 50 BRiTE Registry—Patients with Bevacizumab Beyond Progression (BBP) No postPD Rx (n = 253) No BBP (n = 531) BBP (n = 642) Number of deaths (%) 168 (66%) 306 (58%) 260 (41%) Median OS (mo) 12.6 19.9 31.8 1-year (%) survival rate 52.5 77.3 87.7 Median survival beyond 1st PD (mo) 3.6 9.5 19.2 Evaluable patients on 1st-line bevacizumab (n = 1953) 1st Progression (n = 1445) Physician decision—no randomization No post-PD Rx (n = 253) No BBP (n = 531) BBP (n = 642) PD = progressive disease; BBP = bevacizumab beyond 1st progression. Courtesy of Axel Grothey, MD. Slide 39 of 50 2nd-Line Cetuximab BOND Trial Patients progressed on or within 3 months of irinotecan R A N D O M I Z E Cetuximab n = 111 Irinotecan + cetuximab n = 218 Response (%) TTP Median OS Cetuximab 11 1.5 m 6.9 m 9 2 Irinotecan + cetuximab 23 4.1 m 8.6 m 5 22 Cunningham D, et al. N Engl J Med. 2004;351:337. Grade 3/4 Rash (%) Grade 3/4 Diarrhea (%) Slide 40 of 50 Panitumumab Registration Trial Patients progressed on fluoropyrimidine, oxaliplatin, and irinotecan R A N D O M I Z E Panitumumab + best supportive care (BSC) n = 231 BSC n = 232 Reprinted from Van Cutsem E, et al. J Clin Oncol. 2007;25:1658-1664, with permission from the American Society of Clinical Oncology. Panitumumab n = 176 Slide 41 of 50 Antibody Combination BOND-2 Patients progressed on or within 3 months of irinotecan No prior bevacizumab R A N D O M I Z E Cetuximab + bevacizumab n = 40 Irinotecan + cetuximab + bevacizumab n = 43 Response Rate (%) Time to Progress Grade 3/4 Rash (%) Grade 3/4 Diarrhea (%) Cetuximab + bevacizumab 20 4.9 m 20 0 Cetuximab + bevacizumab + irinotecan 37 7.3 m 21 28 Saltz LB, et al. J Clin Oncol. 2007;25:4557. Slide 42 of 50 Phase III Trial of Irinotecan/FOLFIRI + Cetuximab ± Bevacizumab in Patients with Relapsed MCRC S0600/iBET Previously treated patients with metastatic colorectal cancera (N = 1260) R A N D O M I Z E Irinotecan or FOLFIRI + cetuximab + placebo (q2–3wk) Irinotecan or FOLFIRI + cetuximab + bevacizumab (5 mg/kg q2–3wk) Irinotecan or FOLFIRI + cetuximab + bevacizumab (10 mg/kg q2–3wk) Primary endpoint: OS Secondary endpoint: PFS iBET = Intergroup Bevacizumab Continuation Trial. aPatients progressed on FOLFOX, OPTIMOX, or XELOX + bevacizumab in 1st-line. http://clinicaltrials.gov/ct/show/NCT00499369?order=1. Accessed May 2008. Slide 43 of 50 Question 5 The patient was favoring irinotecan and cetuximab but read in the newspaper that her tumor should be tested first to see if it will respond to cetuximab. Which of the following markers may predict a response to EGFR monoclonal antibody therapy? a) EGFR staining by immunohistochemistry b) K-ras mutational analysis c) VEGF levels in the blood d) EGFR mutational analysis Slide 44 of 50 Predictors of Response to Monoclonal EGFR Inhibitors • Patients with tumors that have K-ras mutations may not benefit from cetuximab or panitumumab • Other potential predictors – Skin toxicity – Amphiregulin and epiregulin • Not predictors – EGFR staining on immunohistochemistry – EGFR mutations (rare in colorectal cancer) Slide 45 of 50 K-ras and Cetuximab Progression-free survival with single-agent cetuximab in laterline metastatic colorectal cancer1 Cetuximab + irinotecan after irinotecan progression2 1. Reprinted from Khambata-Ford S, et al. J Clin Oncol. 2007;25:3230-3237, with permission from the American Society of Clinical Oncology. 2. Reprinted from Lievre A, et al. J Clin Oncol. 2008;26:374-379, with permission from the American Society of Clinical Oncology. Slide 46 of 50 K-ras and Panitumumab K-ras Mutation Wild-Type K-ras Courtesy of Eric Van Custem, MD, Segaert and Van Cutsem. Ann Oncol. 2005. Slide 47 of 50 1st-Line Cetuximab and K-ras Status CRYSTAL Trial R A N D O M I Z E Median Progression-Free Survival n = 599 FOLFIRI FOLFIRI + Cetuximab n = 599 All patients K-ras wildtype K-ras mutant FOLFIRI 8.0 m 8.7 m 8.1 m FOLFIRI + Cetuximab 8.9 m 9.9 m 7.6 m P value .046 .02 .47 Van Cutsem E, et al. ASCO 2008. J Clin Oncol. 2008;26(suppl):abstract 2. Slide 48 of 50 Phase III Trial of Cetuximab, Bevacizumab, and FOLFOX/FOLFIRI CALGB/SWOG 80405 • 1st-line metastatic colorectal cancer • Wt K-ras • Planned accrual: 2600 aPhysician-selected R A N D O M I Z E FOLFOX or FOLFIRIa + bevacizumab FOLFOX or FOLFIRIa + cetuximab FOLFOX or FOLFIRIa + cetuximab + bevacizumab chemotherapy. Stratification based on chemotherapy, prior adjuvant chemotherapy, prior pelvic RT. US NIH Clinical Trials Database. http://www.clinicaltrials.gov/ct2/show/NCT00265850?term=80405&rank=1. Slide 49 of 50 Conclusions • Lifestyle adjustments may impact outcome from colorectal cancer • Biologic agents have a role in advanced disease but their place in the adjuvant setting remains to be determined • The era for individualized colorectal cancer treatments is approaching Slide 50 of 50