Welcome!         The Latest in Colorectal Cancer                    Research        Part of Fight Colorectal Cancer’s Mont...
Fight Colorectal Cancer1. Tonight’s speaker: Dr. Richard Goldberg, MD2. Archived webinars: Link.FightCRC.org/Webinars3. Fo...
Fight Colorectal CancerDisclaimerThe information and services provided by Fight ColorectalCancer are for general informati...
Fight Colorectal Cancer                            March 2013 EventsMarch 1: Times Square Kick Off                        ...
Website: www.ccalliance.org     Helpline: (877) 422-2030My CCA Support Online Community:      www.myccasupport.org
Fight Colorectal Cancer                 Dr. Richard Goldberg, MD                       Physician-in-Chief                 ...
Cancer of the Colon and Rectum:     A Decade of Progress                 Richard M Goldberg M.D.          Klotz Family Cha...
Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012Trends in Incidence Rates: 1975-2008                     ...
Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012US Death Rates in Men & Women:1975-2008     57,100 in 200...
The Genetics of Colorectal Cancer:          Henry Lynch               The Ohio State University Comprehensive Cancer Cente...
Colorectal Cancer: Genetics         15%                                                                                 85...
Revised Lynch Syndrome Screening Criteria          (Amsterdam criteria II) > 3 relatives with an HNPCC-associated cancer ...
Patient & Family Implications: Lynch Syndrome                                          MLH1MSH2    MSH6       PMS2        ...
Screening for the Lynch Syndrome  (Hereditary Nonpolyposis Colorectal Cancer)  Hampel H, Frankel W, Martin E, Arnold M, Kh...
Potential Impact Columbus Project:    44 of 1600 screened had Lynch Syndrome    50% diagnosed over age 50    25% met n...
Genomics:   Comprehensive MolecularCharacterization of Human Colon      and Rectal Cancer    The Cancer Genome Atlas Netwo...
Methods and Key Findings Methods: Whole genome sequencing of 276  colorectal tumors   Exome sequence, DNA copy number, p...
Genomics: Cancer Genome Atlas             The Ohio State University Comprehensive Cancer Center –             Arthur G. Ja...
Significance “While it may take years to translate this  foundational genetic data on colorectal cancers into  new therap...
Abstract 3511. Identification and validationof gene expression subtypes in a large set      of colorectal cancer samples  ...
Novel Subtypes are Characterized by Distinct Biological       Components that Predict Patient Survival                    ...
Subtypes are Validated in Independent Datasets                                                                            ...
Subtype SummaryA – normal -like epithelial: KRAS, differentiated, no CSC markers, Wntdown, good OS and RFSB – proliferativ...
PreventionCharles Fuchs          Robert SandlerJeff Mayerhardt                John Baron                  The Ohio State U...
Colorectal Cancer:         Risk Factors OverviewDecrease Risk      Increase Risk                                         U...
Data from Observational       Studies for Stage I-III Disease Decrease risk of recurrence    Physical activity    Avoid...
Physical Activity and                       Colorectal Cancer  Cohort study from Australia of 526 colorectal cancer patie...
89803 and Exercise: Disease-Free Survival   in Stage III Colon Cancer Survivors                                     1.2  H...
NSABP and Body Mass Index Disease-free and overall survival by body mass index (BMI) category in 4288 patientsfrom Nationa...
Glycemic Load Hazard Ratio for Cancer Recurrence or Death                                                     in Colon Can...
Mortality among Patients with Colorectal Cancer, According toRegular Use or Nonuse of Aspirin after Diagnosis and PIK3CA  ...
Screening   The Ohio State University Comprehensive Cancer Center –   Arthur G. James Cancer Hospital and Richard J. Solov...
Colonoscopic Polypectomy and Long-     Term Prevention of Colorectal-Cancer                   Deaths      Zauber A, Winawe...
National Polyp Study 2602 patients with adenomas removed between  1980-90. CRC deaths expected: 25.4 CRC deaths observe...
DNA Stool Tests and CT Colonography                                                               Perry Pickhardt         ...
Stool DNA Testing Biologically rational                                                      Mucus at Cancer Surface Non...
Detection Rates              at 90% Specificity Cutoffs100      88.890                                                    ...
CT Colonography:        Advanced AdenomaPolyp size 10 mm or >. Prevalence c.5 -7 %                   The Ohio State Univer...
CT Colonography: Issues      Sensitivity: Detection of patients with       adenomas >9mm:                                ...
Surgical TechniquesLaparoscopic                                                       Robotic               The Ohio State...
Laparoscopically Assisted    Versus Open Colectomy For           Colon Cancer            790 patients accrued     Conventi...
COST Outcomes          Conversion   Incision    Time                      LOS                       IV narcs       PO narc...
LAC vs Open Colectomy No difference in    Complication rate       Wound recurrences    30 day mortality (4 open, 2 LAC...
Other Effects     The Ohio State University Comprehensive Cancer Center –     Arthur G. James Cancer Hospital and Richard ...
Rectal CancerZ6051: Lap Rectal Cancer Trial           Eligible pt with stage II-III        primary rectal adenocarcinoma  ...
TME: a comparison of oncological and    functional outcomes between robotic and      laparoscopic surgery for rectal cance...
Liver ResectionGross Anatomy                              Eight Segments                                                  ...
Survival After Liver Resection In Metastatic ColorectalCancer: Review And Meta-analysis Of Prognostic Factors             ...
Types of Chemotherapy-Induced Hepatic InjurySinusoidal        Steatosis                                           Steatohe...
Stereotactic body radiotherapy for            colorectal liver metastasesChang AT, Swaminath A, Kozak M, Weintraub J,Koong...
Steriotactic Radiosurgery 47 patients Median dose: 42 Gray 3 fraction model 1 year local control 92%                  ...
Preoperative versus Postoperative        Chemoradiotherapy for Rectal CancerSauer R, Becker H, Hohenberger W, Rödel C, Wit...
Cumulative Incidence of Local Relapse                               Median Follow-up: 40 months                           ...
German Rectal Cancer Trial               Preop                     Post op                               P-valuePelvic rec...
Advances in the Drug Treatment of CRC1980         1985          1990           1995                            2000       ...
Oxaliplatin Vs 5-FU/LV In                    Adjuvant Therapy                                   MOSAIC & NSABP C-07Aimery ...
MOSAIC Phase III Trial     R     A     N   N=1100               FOLFOX4     D     O     M     I                           ...
Disease-free Survival:              1.0                        Stage II and III Patients              0.9                 ...
MOSAIC OS with >6 Years Follow-up              1.0                                                                     p=0...
NSABP C-07    Stage ll + lll   Stratify: # positive nodes       RandomizeFU/LV                                            ...
Oxaliplatin as adjuvant therapy for colon cancer: updated results of     NSABP C-07 trial, including survival and subset a...
3-year DFS (stage III)                Study       treatment                                                   3-year DFS  ...
Advances In Treatment OfAdvanced Disease Since 2013     Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanthan RK, Willia...
Intergroup Study N9741:    A Combination Chemotherapy Comparison                                                          ...
Phase III Trial of Bevacizumab in            First-Line MCRC                                                              ...
Cetuximab and        PanitumumabCetuximab for the Treatment of Colorectal CancerJonker DJ, OCallaghan CJ, Karapetis C, Zal...
Single Agent CetuximabRAN   Cetuximab* + BSCDOMI      BSC aloneZE                       The Ohio State University Comprehe...
Kaplan–Meier Curves for Progression-freewith Cetuximab alone        Progression Free Survival Survival According to Treatm...
Single Agent PanitumumabRAN   Panitumumab +D        BSCOMI     BSC aloneZE                    The Ohio State University Co...
Single Agent Panitumumab:              N=208K-Ras Mutation                                             Wild-Type K-Ras    ...
Aflibercept and Regorafinib    Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, Ruff P,    van Haze...
FOLFIRI +/- Aflibercept             Aflibercept600 pts             4 mg/kg IV             + FOLFIRIR          Placebo + FO...
Regorafinib505 pts   Regorafinib po             + BSCR            Placebo255 pts             + BSC                        ...
Progression-Free SurvivalRegorafenib      Cetuximab                                                   Panitumumab         ...
Advances in the Treatment of Stage IV CRC         1980          1985     1990      1995              2000                 ...
Guidelines:    Association Between Adherence To     National Comprehensive Cancer    Network Treatment Guidelines And    I...
Guidelines   The Ohio State University Comprehensive Cancer Center –   Arthur G. James Cancer Hospital and Richard J. Solo...
Adjuvant Therapy of Colon Cancer National Cancer Database 1998-2002 High risk Stage II and Stage III 167,434 patients ...
A Decade of Progress Declining mortality by > 10% Potential for universal Lynch Syndrome screening Unraveling the myste...
Fight Colorectal Cancerwww.FightColorectalCancer.org877-427-2111
Fight Colorectal Cancer                               CONTACT US    Fight Colorectal Cancer      1414 Prince Street, Suite...
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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 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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The Latest in Colorectal Cancer Research

  1. 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. 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. 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. 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. 5. Website: www.ccalliance.org Helpline: (877) 422-2030My CCA Support Online Community: www.myccasupport.org
  6. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 32. Screening The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 32
  33. 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. 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. 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. 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. 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. 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. 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. 40. Surgical TechniquesLaparoscopic Robotic The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 40
  41. 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. 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. 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. 44. Other Effects The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 44
  45. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 77. Guidelines The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 77
  78. 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. 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. 80. Fight Colorectal Cancerwww.FightColorectalCancer.org877-427-2111
  81. 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
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