Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Cancer of the Colon and Rectum: A Decade of Progress Richard M Goldberg M.D. Klotz Family Chair in Cancer Research Professor and James Cancer Hospital Physician-in-Chief The Ohio State University Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012 Trends in Incidence Rates: 1975-2008 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 2 Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012 US Death Rates in Men & Women:1975-2008 57,100 in 2003 & 51,690 in 2012 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 3 The Genetics of Colorectal Cancer: Henry Lynch The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 4 Colorectal Cancer: Genetics 85% 15% CIN (Chromosome Instability) MIN (MSI+) (Microsatellite Instability) 2-3% Lynch Sx Germline Mutation MMR genes MLH1, MSH2, MSH6 & PMS2 13% <1% Sporadic MSI(+) •Epigenetic silencing of MLH1 by hypermethylation of its promoter region FAP Germline Mutation APC The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 85% Sporadic Acquired APC, p53, DCC, kras, LOH,... 5 Revised Lynch Syndrome Screening Criteria (Amsterdam criteria II) > 3 relatives with an HNPCC-associated cancer (CRC, cancer of the endometrium, small bowel, ureter, or renal pelvis) One should be a first-degree relative of the other 2 At least 2 successive generations should be affected At least 1 should be diagnosed before age 50 Familial adenomatous polyposis should be excluded in the CRC case(s) if any Tumors should be verified by pathological exam Vasen, Gastroenterology, 116: 1453-6, 1999 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 6 Patient & Family Implications: Lynch Syndrome MLH1 MSH2 MSH6 PMS2 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 7 Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Hampel H, Frankel W, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa H, Sotamaa K, Prior T, Westman J, Panescu J, Fix D, Lockman J, Comeras I, and de la Chapelle A. Albert de la Chapelle Heather Hampel N Engl J MedMed Volume 352:1851-1860, 2005 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 8 Potential Impact Columbus Project: 44 of 1600 screened had Lynch Syndrome 50% diagnosed over age 50 25% met neither Amsterdam or Bethesda criteria Ohio Colorectal Cancer Prevention Initiative Nationally 143,460 new cases of CRC in the US in 2013 4,016 have Lynch syndrome (2.8%) 12,050 of their relatives have LS (~3 per proband) Total of 15,816 individuals who could be diagnosed with Lynch Syndrome with universal screening American Cancer Society Facts & Figures The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 9 Genomics: Comprehensive Molecular Characterization of Human Colon and Rectal Cancer The Cancer Genome Atlas Network Nature 487: 330-337, 2012 Raju Kucherlapati The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 10 Methods and Key Findings Methods: Whole genome sequencing of 276 colorectal tumors Exome sequence, DNA copy number, promotor methylation, messenger and micro RNA expression Key Findings 16% hypermutated; 75% MSI-H Colon and rectal cancers share similar patterns of genomic alteration 24 genes significantly mutated: Expected: APC, TP53, SMAD4, PIK3CA, KRAS Unexpected: ARID1A, SOX9, FAM123B, ERBB2 Potential new targets: ERBB2, IGF2 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 11 Genomics: Cancer Genome Atlas The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 12 Significance “While it may take years to translate this foundational genetic data on colorectal cancers into new therapeutic strategies and surveillance methods, this genetic information unquestionably will be the springboard for determining what will be useful clinically against colorectal cancers,” said Harold Varmus, NCI director. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 13 Abstract 3511. Identification and validation of gene expression subtypes in a large set of colorectal cancer samples PETACC3 + public datasets E Budinska, V Popovici, S Tejpar, N Lapique, K Otylia Sikora, AF Di Narzo, JG Hodgson, S 6 8 Weinrich, F Bosman, A Roth , M Delorenzi J Clin Oncol 30, 2012 (suppl; abstr 3511) Sabine Tejpar The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 14 Novel Subtypes are Characterized by Distinct Biological Components that Predict Patient Survival The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 15 Subtypes are Validated in Independent Datasets Based on the set of gene modules derived , we performed subtype derivation in the validation set. While subtypes A, C, D and E appeared in the Larger datasets are needed to confirm and further study additional subtypes. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 16 Subtype Summary A – normal -like epithelial: KRAS, differentiated, no CSC markers, Wnt down, good OS and RFS B – proliferative epithelial: differentiated, but lost secretory cells, proliferative, 20q genes up, Wnt active, MSS, nonBRAF, non-mucinous, good OS, RFS, SAR C – CIMP-H like: undifferentiated carcinomas, MSI, BRAF, mucinous, right, less frequently p53 mutated, enriched in females, proliferative, immune, CIMP+, the shortest SAR, poor OS D – mesenchymal: no proliferation, high CSC markers, Wnt inactive, active EMT, the shortest RFS, poor OS and SAR E – intermediate: MSS, nonBRAF, non mucinous, left, CSC markers, EMT, proliferation, differentiation, p53 enriched The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 17 Prevention Charles Fuchs Jeff Mayerhardt Robert Sandler John Baron The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 18 Colorectal Cancer: Risk Factors Overview Decrease Risk Screening Exercise Aspirin / NSAIDs Vitamin D Post-menopausal estrogen Calcium Increase Risk Family history Ulcerative colitis/ Crohn’s Disease Diabetes Obesity Red meat Western diet Alcohol Smoking Uncertain Impact Statins Fiber Glycemic load Fruits/Vegetables Folic Acid The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 19 Data from Observational Studies for Stage I-III Disease Decrease risk of recurrence Physical activity Avoidance of Western pattern diet Avoidance of class II/ III obesity (BMI > 35 kg/m2) Aspirin or COX-2 inhibitor Higher vitamin D levels No association with recurrence to date Weight change (gain or loss) Smoking status or history Multivitamin The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Credits: Charles Fuchs Jeffrey Meyerhardt Brian Wolpin Kimmie Ng Andrew Chan Nadine McCleary Donna Niedzwiecki Donna Hollis CALGB 20 Physical Activity and Colorectal Cancer Cohort study from Australia of 526 colorectal cancer patients with pre-diagnosis physical activity assessment Van Loon K, Wigler D, Niedzwiecki D, Venook AP, Fuchs C, Blanke C, Saltz L, Goldberg RM, Meyerhardt JA, Clin Colorectal Cancer. Epub ahead of print 1/11/ 2013 Colorectal cancer specific survival The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 21 Haydon Gut. 2006 Jan;55(1):62-7 89803 and Exercise: Disease-Free Survival in Stage III Colon Cancer Survivors Hazard Ratio Recurrence or Death 1.2 1 0.8 0.6 0.4 0.2 0 <3 3-8.9 9-17.9 18.0-26.9 >27 Regular Physical Activity (met-hours per week) The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 22 Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006 NSABP and Body Mass Index Disease-free and overall survival by body mass index (BMI) category in 4288 patients from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials for Dukes B and C colon cancer The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 23 Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654 Hazard Ratio for Cancer Recurrence or Death Glycemic Load in Colon Cancer Patients 2.5 2.26 2 1.7 1.5 1 1 0.99 1.07 1 1 0.81 0.5 0.65 0.91 BMI < 25 0 1 2 3 4 5 Quintiles of Glycemic Load Meyerhardt JA Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Natl Cancer Inst.104:1702-11, 2012. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Meyerhardt, Research Institute J. et al JNCI 2012 24 Mortality among Patients with Colorectal Cancer, According to Regular Use or Nonuse of Aspirin after Diagnosis and PIK3CA Mutation Status. Liao X et al. N Engl J Med 367:1596-1606, 2012. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 25 Screening The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 26 Colonoscopic Polypectomy and LongTerm Prevention of Colorectal-Cancer Deaths Zauber A, Winawer SJ, O’Brien MJ, Lansdorp-Vogelaar I, van Ballegooijen M, Hankey BF, Shi W, Bond JH, Schapiro M, Panish JF, Stewart ET, and Waye JD. N Engl J Med 366:687-96, 2012. Ann Zauber The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 27 National Polyp Study 2602 patients with adenomas removed between 1980-90. CRC deaths expected: 25.4 CRC deaths observed: 12 53% reduction in mortality These findings support the hypothesis that colonoscopic removal of adenomatous polyps prevents death from colorectal cancer. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 28 DNA Stool Tests and CT Colonography Perry Pickhardt Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, Taylor WR, Butz ML, Thibodeau SN, Rabeneck L, Paszat LF, Kinzler KW, Vogelstein B, Bjerregaard NC, Laurberg S, Sørensen HT, Berger BM, Lidgard GP. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology. 142:248-56, 2012 Pickhardt PJ, Choi JR, Hwang I, Butler JA, Puckett ML, Hildebrandt HA, Wong RK, Nugent PA, Mysliwiec PA, Schindler WR. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med. 349:2191-200, 2003. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 29 Stool DNA Testing Biologically rational Mucus at Cancer Surface Noninvasive No cathartic preparation No diet or med restriction Off-site collection Normal Widely accessible Not affected by lesion site Adenoma High sensitivity for both CRC & precancer The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 30 Detection Rates at 90% Specificity Cutoffs 100 90 88.8 85.3 Covariate analysis 78.1 80 70 63.9 63.6 63.8 60 CRC 50 Adenoma >1cm 40 30 20 10 0 Training Set Test Set Combined Set The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 31 31 CT Colonography: Advanced Adenoma Polyp size 10 mm or >. Prevalence c.5 -7 % The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 32 CT Colonography: Issues Sensitivity: Detection of patients with adenomas >9mm: Pickhardt Cotton Rockey Sensitivity 94% 55% 59% Specificity 96% 96% 96% NEJM 2003; 349: 2191; JAMA 2004; 291:1713-9; Rockey: Lancet 2005;365: 305-11 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 33 Surgical Techniques Laparoscopic Robotic The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 34 Laparoscopically Assisted Versus Open Colectomy For Colon Cancer 790 patients accrued Conventional Colectomy R Laparoscopic Colectomy (LAC) Heidi Nelson N Engl J Med 351:933-934, 2004 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 35 COST Outcomes Conversion rate Incision Cm Time Minutes LOS Days IV narcs Days PO narcs days LAC 21% 6 150 5 3 1 Open NA 18 95 6 4 2 <.001 <.001 <.001 <.001 <.02 P-value The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 36 LAC vs Open Colectomy No difference in Complication rate Wound recurrences 30 day mortality (4 open, 2 LAC) Disease free survival Overall survival Equivalent cancer procedures Weeks, JAMA 2002 Nelson, NEJM 2004 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 37 Other Effects s The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 38 Rectal Cancer Z6051: Lap Rectal Cancer Trial Eligible pt with stage II-III primary rectal adenocarcinoma by ERUS or MRI staging Randomization Open rectal resection Laparoscopic rectal resection The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 39 TME: a comparison of oncological and functional outcomes between robotic and laparoscopic surgery for rectal cancer. # Pts Time min Med # nodes Margin < 2 mm Efficacy Robotic 50 270 16.5 0 ? Laparoscopic 50 275 13.8 6 ? D'Annibale A, Pernazza G, Monsellato I, Pende V, Lucandri G, Mazzocchi P, Alfano G. Surg Endosc. Epub ahead of print, Jan 5, 2013 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 40 Liver Resection Gross Anatomy Eight Segments Rene Adam The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 41 Survival After Liver Resection In Metastatic Colorectal Cancer: Review And Meta-analysis Of Prognostic Factors 3-yr survival 5-yr survival (%) (%) Median survival years All 58% 40% 3.6 years Solitary 61 47 3.6 Extrahepatic 40 24 3.6 Isolated 54 39 3.2 Periop chemo 55 37 3.3 Resectable at Dx 55 41 3.3 Synchronous 46 37 3.2 Metachronous 58 43 3.3 Kanas GP, Taylor A, Primrose JN, Langeberg W, Kelsh MA, Mowat FS, Alexander DD, Choti MA, and Poston G. Clin Epidemiol. 4: 283–301, 2012. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 42 Types of Chemotherapy-Induced Hepatic Injury Sinusoidal Dilatation Steatosis Steatohepatitis (NASH) The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 43 Stereotactic body radiotherapy for colorectal liver metastases Chang AT, Swaminath A, Kozak M, Weintraub J,Koong AC, John Kim J, Dinniwell R, Brierley J, Kavanagh BD, Dawson LA, Schefter TE. Cancer 117:4060–4069, 2011 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 44 Steriotactic Radiosurgery 47 patients Median dose: 42 Gray 3 fraction model 1 year local control 92% Daniel Chang The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 45 Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens J-H, Liersch T, Schmidberger H, and Raab R for the German Rectal Cancer Study Group Locally advanced rectal cancer Radiation pre vs post operatively 5-FU chemotherapy TME 823 pts randomized Median follow up now 10 years N Engl J Med 351:1731-174, 2004. J Clin Oncol. 30:1926-33, 2012 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 46 Cumulative Incidence of Local Relapse Locoregional Recurrences Median Follow-up: 40 months .14 .12 .10 12% Post-op CRT .08 .06 6% .04 .02 0.00 p = 0.006 Pre-op CRT 0 10 20 30 40 50 60 Months The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 47 German Rectal Cancer Trial Pelvic recur Distant recur Survival Gr 3-4 tox Anastomotic stenosis APR Preop Post op P-value 6% 12% 0.006 29.8% 29.6% 0.90 59.6% 59.9% 0.9 29% 32% N.S. 2.7% 8.5% 0.001 39% 19% 0.004 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 48 Advances in the Drug Treatment of CRC 1980 1985 1990 5-FU Hanna Kelly Sanoff 1995 2000 2005 2013 Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Aflibercept Regorafinib Therapeutic concepts Palliative chemotherapy Adjuvant chemotherapy Neoadjuvant chemotherapy Updated from Kelly and Goldberg. J Clin Oncol. 2005;23:4553 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 49 Oxaliplatin Vs 5-FU/LV In Adjuvant Therapy MOSAIC & NSABP C-07 Aimery de Gramont Thierry Andre Greg Yothers Norman Wolmark André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer: MOSAIC Investigators. N Engl J Med 350: 2343–51, 2004. Yothers G, O'Connell MJ, Allegra CJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: Updated results of NSABP C-07, including survival and subset analyses. J Clin Oncol 29:3768–74, 2011. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 50 MOSAIC Phase III Trial R A N D O M I Z A T I O N N=1100 FOLFOX4 • 40% Stage II • 60% Stage III N=1100 LV5FU2 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 51 Disease-free Survival: Stage II and III Patients 1.0 0.9 p=0.258 0.8 Probability 3.8% p=0.005 0.7 0.6 7.5% 0.5 0.4 FOLFOX4 stage II 0.3 LV5FU2 stage II 0.2 FOLFOX4 stage III 0.1 LV5FU2 stage III 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 52 MOSAIC OS with >6 Years Follow-up 1.0 p=0.996 0.9 Probability 0.8 p=0.029 0.1% 0.7 4.4% 0.6 0.5 0.4 0.3 FOLFOX4 stage II 0.2 LV5FU2 stage II 0.1 FOLFOX4 stage III LV5FU2 stage III 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Overall survival (months) The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 53 NSABP C-07 Stage ll + lll Stratify: # positive nodes Randomize FU/LV FLOX The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 54 Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 55 3-year DFS (stage III) monotherapy no RX Study treatment 3-year DFS Moertel Observation 52% IMPACT Observation 44% IMPACT Punt 5FU/LV 5FU/LV 62% 65% Fields 5FU/LV 67% André 5FU/LV 61% MOSAIC 5FU/LV 65% X-Act Capecitabine 64% FOLFOX4 FLOX 73% 76% 2 drugs MOSAIC C-07 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 56 Advances In Treatment Of Advanced Disease Since 2013 Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanthan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SA. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22: 23-30, 2004. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S., Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer, N Engl J Med 350:2335-2342, 2004. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 57 Intergroup Study N9741: A Combination Chemotherapy Comparison IFL (median 15.0 mo) FOLFOX4 (median 19.5 mo) IROX (median 17.4 mo) 100 n=267 n=264 n=264 90 FOLFOX4: oxaliplatin + infusional 5-FU/LV IFL: irinotecan + bolus 5-FU/LV IROX: oxaliplatin + irinotecan 80 % of patients R A N D O M I Z A T I O N 70 60 50 40 30 20 FOLFOX4 vs IFL P=0.0001; HR=0.66 10 IROX vs IFL P=0.04; HR=0.81 FOLFOX4 vs IROX P=0.09; HR=0.83 0 0 1 2 Years The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 58 Phase III Trial of Bevacizumab in FirstLine MCRC IFL + placebo IFL + placebo = 15.1 IFL + bevacizumab = 20.5 5-FU/LV + bevacizumab = 18.3 (n=411) 0.8 IFL + bevacizumab (5 mg/kg, q2w) (n=402) 5-FU/LV + bevacizumab* (5 mg/kg, q2w) (n=110) Proportion surviving R A N D O M I Z A T I O N Median Survival (mo) 1.0 0.6 0.4 Treatment Group IFL + placebo (n=101)* IFL + bevacizumab (n=103)* 5-FU/LV + bevacizumab (n=110) 0.2 0 0 10 25 30 40 Months The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 59 Cetuximab and Panitumumab Cetuximab for the Treatment of Colorectal Cancer Jonker DJ, O'Callaghan CJ, Karapetis C, Zalcberg JR, Tu D, Au H-J, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, and Moore MJ. N Engl J Med 2007; 357:2040-2048 Van Cutsem E, Peeters M, Salvatore Siena S, Humble Y, Hendlisz A, Neyns B, Canon J-L, Van Laethem J-L, Maurel J, Richardson G, Wolf M, and Amado RG. Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer, J Clin Oncol. 25:1658-1664, 2007. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 60 Single Agent Cetuximab R A N D O M I Z E Cetuximab* + BSC BSC alone The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 61 Kaplan–Meier Curves for Progression-free Survival Accordingalone to Treatment. Progression Free Survival with Cetuximab Correlated with K-ras Status Karapetis CS et al. N Engl J Med 2008;359:17571765. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 62 Single Agent Panitumumab R A N D O M I Z E Panitumumab + BSC BSC alone The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 63 Single Agent Panitumumab: N=208 K-Ras Mutation Wild-Type K-Ras Panitumumab registration trial The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 64 Aflibercept and Regorafinib Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition Of Aflibercept To Fluorouracil, Leucovorin, And Irinotecan Improves Survival In A Phase III Randomized Trial In Patients With Metastatic Colorectal Cancer Previously Treated With An Oxaliplatin-based Regimen. J Clin Oncol. 30:3499-506, 2012. Grothey A, Cutsem EV, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; for the CORRECT Study Group. Regorafenib monotherapy for previously treatedmetastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. Epub Nov 21 2012. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 65 FOLFIRI +/- Aflibercept 600 pts Aflibercept 4 mg/kg IV + FOLFIRI R 600 pts Placebo + FOLFIRI The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 66 Regorafinib 505 pts Regorafinib po + BSC R 255 pts Placebo + BSC The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 67 Progression-Free Survival Regorafenib Cetuximab The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Panitumumab 68 Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005 2010 2015 BSC 35 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Panitumumab 30 OS (months) 25 20 15 Aflibercept Regorafenib BBP 10 median overall survival 5 0 1980 1985 1990 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 1995 2000 2005 2010 69 2015 Guidelines: Association Between Adherence To National Comprehensive Cancer Network Treatment Guidelines And Improved Survival In Patients With Colon Cancer. Boland GM, Chang GJ, Haynes AB, Chiang YJ, Chagpar R, Xing Y, Hu CY, Feig BW, You YN, Cormier JN. Cancer. Epub ahead of print Dec 21, 2012 Janice Cormier The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Guidelines The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 71 Adjuvant Therapy of Colon Cancer National Cancer Database 1998-2002 High risk Stage II and Stage III 167,434 patients Rates of guideline adherence 36% for high-risk stage II 74% Stage III 5-year survival versus adherence to guidelines Yes: 67.7% No: 54.5% The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 72 A Decade of Progress Declining mortality by > 10% Potential for universal Lynch Syndrome screening Unraveling the mysteries of the genome Prevention & prevention of recurrence New screening tools: fecal DNA, CT colonograpy Laparoscopic, robotic and hepatic surgery Preoperative rectal radiation and Cyberknife Oxaliplatin, bevacizumab, cetuximab, panitumumab, aflibercept, regorafinib The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 73