The Latest in Colorectal Cancer Research

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Each January, the best and brightest minds in colorectal cancer research meet at the Gastrointestinal Cancers Symposium. Fight Colorectal Cancer and the Colon Cancer Alliance are partnering to bring …

Each January, the best and brightest minds in colorectal cancer research meet at the Gastrointestinal Cancers Symposium. Fight Colorectal Cancer and the Colon Cancer Alliance are partnering to bring you the big news in colorectal cancer from the 2013 symposium.

Join us to learn more about these topics:

- Can aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) keep cancer from returning?
- The relationship of body mass index (BMI) and exercise in colorectal cancer
- What scientists are learning about how your immune system can fight cancer
- The latest on what biomarkers can tell us about your cancer
- Rectal cancer treatment that is based on your biological make-up

The webinar will be led by Dr. Richard Goldberg, an internationally renowned gastrointestinal oncologist who specializes in colorectal cancer. He is a tenured professor in the Department of Internal Medicine at The Ohio State University and serves as physician-in-chief at Ohio State’s Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

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  • 1. Welcome! The Latest in Colorectal Cancer Research Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series Our webinar will begin shortlywww.FightColorectalCancer.org877-427-2111
  • 2. Fight Colorectal Cancer1. Tonight’s speaker: Dr. Richard Goldberg, MD2. Archived webinars: Link.FightCRC.org/Webinars3. Follow up survey to come via email. Get a free Blue Star ofHope pin when you tell us how we did tonight.4. Ask a question in the panel on the right side of your screen andlook for hyperlinks during throughout the presentation.5. Or call the Fight Colorectal Cancer Answer Line at 877-427-2111 www.FightColorectalCancer.org 877-427-2111
  • 3. Fight Colorectal CancerDisclaimerThe information and services provided by Fight ColorectalCancer are for general informational purposes only.The information and services are not intended to be substitutesfor professional medical advice, diagnosis, or treatment.If you are ill, or suspect that you are ill, see a doctorimmediately. In an emergency, call 911 or go to the nearestemergency room.Fight Colorectal Cancer never recommends or endorses anyspecific physicians, products or treatments for any condition.www.FightColorectalCancer.org877-427-2111
  • 4. Fight Colorectal Cancer March 2013 EventsMarch 1: Times Square Kick Off March 18-20: Call-on Congress Registration closes on Feb. 22nd! www.FightColorectalCancer.org March 20: Congressional Call-In Unite behind a cure! Join our one-day phone blitz to Congress www.FightColorectalCancer.org 877-427-2111
  • 5. Website: www.ccalliance.org Helpline: (877) 422-2030My CCA Support Online Community: www.myccasupport.org
  • 6. Fight Colorectal Cancer Dr. Richard Goldberg, MD Physician-in-Chief Professor of Medicine The Klotz Family Chair in Cancer Research Associate Director of Outreach The Ohio State University Comprehensive Cancer Centerwww.FightColorectalCancer.org877-427-2111
  • 7. 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
  • 8. Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012Trends in Incidence Rates: 1975-2008 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 8
  • 9. Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012US 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 9
  • 10. 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 10
  • 11. Colorectal Cancer: Genetics 15% 85% MIN (MSI+) CIN (Microsatellite Instability) (Chromosome Instability) 2-3% 13% <1% 85% FAP Sporadic Lynch Sx Sporadic MSI(+) Germline AcquiredGermline Mutation Mutation APC, p53,MMR genes •Epigenetic silencing of APC DCC, kras,MLH1, MSH2, MLH1 by hypermethylation LOH,...MSH6 & PMS2 of its promoter region The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 11
  • 12. 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 12
  • 13. Patient & Family Implications: Lynch Syndrome MLH1MSH2 MSH6 PMS2 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 13
  • 14. Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Hampel H, Frankel W, Martin E, Arnold M, Khanduja K, Kuebler P, NakagawaH, Sotamaa K, Prior T, Westman J, Panescu J, Fix D, Lockman J, Comeras I, and de la Chapelle A.Heather Hampel Albert de la Chapelle 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 14
  • 15. 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 15
  • 16. Genomics: Comprehensive MolecularCharacterization 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 16
  • 17. 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 17
  • 18. Genomics: Cancer Genome Atlas The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 18
  • 19. 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 19
  • 20. Abstract 3511. Identification and validationof gene expression subtypes in a large set of colorectal cancer samples PETACC3 + public datasetsE 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 20
  • 21. 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 21
  • 22. 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 22
  • 23. Subtype SummaryA – normal -like epithelial: KRAS, differentiated, no CSC markers, Wntdown, good OS and RFSB – proliferative epithelial: differentiated, but lost secretorycells, proliferative, 20q genes up, Wnt active, MSS, nonBRAF, non-mucinous, good OS, RFS, SARC – CIMP-H like: undifferentiatedcarcinomas, MSI, BRAF, mucinous, right, less frequently p53mutated, enriched in females, proliferative, immune, CIMP+, the shortestSAR, poor OSD – mesenchymal: no proliferation, high CSC markers, Wntinactive, active EMT, the shortest RFS, poor OS and SARE – intermediate: MSS, nonBRAF, non mucinous, left, CSCmarkers, EMT, proliferation, differentiation, p53 enriched The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 23
  • 24. PreventionCharles Fuchs Robert SandlerJeff Mayerhardt John Baron The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 24
  • 25. Colorectal Cancer: Risk Factors OverviewDecrease Risk Increase Risk Uncertain ImpactScreening Family history StatinsExercise Ulcerative colitis/ FiberAspirin / NSAIDs Crohn’s Disease Glycemic loadVitamin D Diabetes Fruits/VegetablesPost-menopausal Obesity Folic Acid estrogen Red meatCalcium Western diet Alcohol Smoking The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 25
  • 26. 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 Credits: Charles Fuchs Jeffrey Meyerhardt No association with recurrence to date Brian Wolpin Kimmie Ng  Weight change (gain or loss) Andrew Chan  Smoking status or history Nadine McCleary Donna Niedzwiecki  Multivitamin Donna Hollis CALGB The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 26
  • 27. Physical Activity and Colorectal Cancer  Cohort study from Australia of 526 colorectal cancer patients with pre-diagnosis physical activity assessmentVan 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 27 Haydon Gut. 2006 Jan;55(1):62-7
  • 28. 89803 and Exercise: Disease-Free Survival in Stage III Colon Cancer Survivors 1.2 Hazard Ratio Recurrence or Death 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 28 Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006
  • 29. NSABP and Body Mass Index Disease-free and overall survival by body mass index (BMI) category in 4288 patientsfrom 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 Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654 29
  • 30. Glycemic Load Hazard Ratio for Cancer Recurrence or Death in Colon Cancer Patients 2.5 2.26 2 1.7 1.5 1 1.07 0.99 1 1 1 0.91 0.81 0.5 0.65 BMI < 25 0 1 2 3 4 5 Quintiles of Glycemic LoadMeyerhardt JA Dietary glycemic load and cancer recurrence and survival in patients withstage 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 Research Institute Meyerhardt, J. et al JNCI 2012 30
  • 31. Mortality among Patients with Colorectal Cancer, According toRegular 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 31
  • 32. Screening The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 32
  • 33. Colonoscopic Polypectomy and Long- Term Prevention of Colorectal-Cancer Deaths Zauber A, Winawer SJ, O’Brien MJ, Lansdorp-VogelaarI, 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 33
  • 34. 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 34
  • 35. 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 35
  • 36. 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 36
  • 37. Detection Rates at 90% Specificity Cutoffs100 88.890 85.3 Covariate80 78.1 analysis70 63.9 63.6 63.86050 CRC Adenoma >1cm40302010 0 Training Set Test Set Ohio State University Comprehensive Cancer Center – The Combined Set Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 37 37
  • 38. CT Colonography: Advanced AdenomaPolyp 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 38
  • 39. CT Colonography: Issues  Sensitivity: Detection of patients with adenomas >9mm: Sensitivity Specificity Pickhardt 94% 96% Cotton 55% 96% Rockey 59% 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 39
  • 40. Surgical TechniquesLaparoscopic Robotic The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 40
  • 41. Laparoscopically Assisted Versus Open Colectomy For Colon Cancer 790 patients accrued Conventional ColectomyR 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 41
  • 42. COST Outcomes Conversion Incision Time LOS IV narcs PO narcs rate Cm Minutes Days Days daysLAC 21% 6 150 5 3 1Open NA 18 95 6 4 2P-value <.001 <.001 <.001 <.001 <.02 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 42
  • 43. 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 43
  • 44. Other Effects The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 44
  • 45. Rectal CancerZ6051: Lap Rectal Cancer Trial Eligible pt with stage II-III primary rectal adenocarcinoma by ERUS or MRI staging Randomization Open Laparoscopic rectal resection rectal resection The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 45
  • 46. TME: a comparison of oncological and functional outcomes between robotic and laparoscopic surgery for rectal cancer. # Pts Time Med # Margin Efficacy min nodes < 2 mmRobotic 50 270 16.5 0 ?Laparoscopic 50 275 13.8 6 ?DAnnibale 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 46
  • 47. Liver ResectionGross Anatomy Eight Segments Rene Adam The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 47
  • 48. Survival After Liver Resection In Metastatic ColorectalCancer: 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 3.3Kanas 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 48
  • 49. Types of Chemotherapy-Induced Hepatic InjurySinusoidal Steatosis SteatohepatitisDilatation (NASH) The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 49
  • 50. Stereotactic body radiotherapy for colorectal liver metastasesChang 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 50
  • 51. 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 51
  • 52. Preoperative versus Postoperative Chemoradiotherapy for Rectal CancerSauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, MartusP, 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 52
  • 53. Cumulative Incidence of Local Relapse Median Follow-up: 40 months .14 Locoregional Recurrences .12 .10 12% Post-op CRT .08 .06 .04 6% .02 Pre-op CRT p = 0.006 0.00 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 53
  • 54. German Rectal Cancer Trial Preop Post op P-valuePelvic recur 6% 12% 0.006Distant 29.8% 29.6% 0.90recurSurvival 59.6% 59.9% 0.9Gr 3-4 tox 29% 32% N.S.Anastomotic 2.7% 8.5% 0.001stenosisAPR 39% 19% 0.004 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 54
  • 55. Advances in the Drug Treatment of CRC1980 1985 1990 1995 2000 2005 2013 5-FUHanna Kelly Sanoff Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Aflibercept RegorafinibTherapeutic 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 55
  • 56. Oxaliplatin Vs 5-FU/LV In Adjuvant Therapy MOSAIC & NSABP C-07Aimery de Gramont Thierry Andre Greg Yothers Norman WolmarkAndré T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvanttreatment for colon cancer: MOSAIC Investigators. N Engl J Med 350: 2343–51, 2004.Yothers G, OConnell 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 56
  • 57. MOSAIC Phase III Trial R A N N=1100 FOLFOX4 D O M I • 40% Stage II Z • 60% Stage III A T I O N=1100 LV5FU2 N The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 57
  • 58. Disease-free Survival: 1.0 Stage II and III Patients 0.9 p=0.258 0.8 3.8% 0.7 p=0.005Probability 0.6 0.5 7.5% 0.4 0.3 FOLFOX4 stage II 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 58
  • 59. MOSAIC OS with >6 Years Follow-up 1.0 p=0.996 0.9 0.8 p=0.029 0.1% 0.7Probability 0.6 4.4% 0.5 0.4 0.3 FOLFOX4 stage II 0.2 LV5FU2 stage II 0.1 FOLFOX4 stage III 0 LV5FU2 stage III 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 59
  • 60. NSABP C-07 Stage ll + lll Stratify: # positive nodes RandomizeFU/LV FLOX The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 60
  • 61. 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 61
  • 62. 3-year DFS (stage III) Study treatment 3-year DFS Moertel Observation 52% no RX IMPACT Observation 44% IMPACT 5FU/LV 62% monotherapy Punt 5FU/LV 65% Fields 5FU/LV 67% André 5FU/LV 61% MOSAIC 5FU/LV 65% X-Act Capecitabine 64%2 drugs MOSAIC FOLFOX4 73% C-07 FLOX 76% The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 62
  • 63. Advances In Treatment OfAdvanced 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 63
  • 64. Intergroup Study N9741: A Combination Chemotherapy Comparison IFL (median 15.0 mo) FOLFOX4 (median 19.5 mo) 100 IROX (median 17.4 mo)R n=267 90 FOLFOX4: oxaliplatinA + infusional 5-FU/LV 80N % of patientsD 70O IFL: irinotecan + 60M n=264I bolus 50Z 5-FU/LVA 40T 30I n=264 IROX: oxaliplatin +O 20 FOLFOX4 vs IFL P=0.0001; HR=0.66N irinotecan 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 64
  • 65. Phase III Trial of Bevacizumab in First-Line MCRC Median Survival (mo)R 1.0 IFL + placebo = 15.1A IFL + placebo IFL + bevacizumab = 20.5N (n=411) 5-FU/LV + bevacizumab =DO 0.8 18.3 Proportion survivingM IFL + bevacizumabIZ (5 mg/kg, q2w) (n=402)A 0.6TI 5-FU/LV + bevacizumab*O (5 mg/kg, q2w) (n=110)N 0.4 Treatment Group IFL + placebo (n=101)* 0.2 IFL + bevacizumab (n=103)* 5-FU/LV + bevacizumab (n=110) 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 65
  • 66. Cetuximab and PanitumumabCetuximab for the Treatment of Colorectal CancerJonker DJ, OCallaghan 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; 357:2040-2048Van 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 ComparedWith Best Supportive Care Alone in Patients With Chemotherapy-RefractoryMetastatic 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 66
  • 67. Single Agent CetuximabRAN Cetuximab* + BSCDOMI BSC aloneZE The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 67
  • 68. Kaplan–Meier Curves for Progression-freewith Cetuximab alone Progression Free Survival Survival According to Treatment. Correlated with K-ras Status Karapetis CS et al. N Engl J Med 2008;359:1757- 1765. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 68
  • 69. Single Agent PanitumumabRAN Panitumumab +D BSCOMI BSC aloneZE The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 69
  • 70. Single Agent Panitumumab: N=208K-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 70
  • 71. 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 71
  • 72. FOLFIRI +/- Aflibercept Aflibercept600 pts 4 mg/kg IV + FOLFIRIR Placebo + FOLFIRI600 pts The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 72
  • 73. Regorafinib505 pts Regorafinib po + BSCR Placebo255 pts + BSC The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 73
  • 74. Progression-Free SurvivalRegorafenib Cetuximab Panitumumab The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 74
  • 75. Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005 2010 2015 BSC 35 5-FU Irinotecan 30 Capecitabine 25 Oxaliplatin CetuximabOS (months) 20 Bevacizumab Panitumumab 15 Aflibercept 10 Regorafenib median overall survival BBP 5 The Ohio State University Comprehensive Cancer Center – 0 Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 75 1980 1985 1990 1995 2000 2005 2010 2015
  • 76. 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
  • 77. Guidelines The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 77
  • 78. 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 78
  • 79. 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 colonography 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 79
  • 80. Fight Colorectal Cancerwww.FightColorectalCancer.org877-427-2111
  • 81. Fight Colorectal Cancer CONTACT US Fight Colorectal Cancer 1414 Prince Street, Suite 204 Alexandria, VA 22314 (703) 548-1225 Toll-Free Answer Line: 1-877-427-2111 www.FightColorectalCancer.orgEmail us: Info@FightColorectalCancer.org