1. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria COLORECTAL CANCER

2. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria COLORECTAL CANCER Worldwide incidence* *Incidence per 100,000 population. Parkin DM, et al. CA Cancer J Clin. 1999;49:33-64. Male39.8 Female29.0 Male25.3 Female18.5 Male39.5 Female24.6 Male45.8 Female34.8 Male5.0 Female3.8 Male6.0 Female4.2 Male11.2 Female 8.5 Male8.8 Female7.9 Male44.3 Female32.8 EasternEurope Japan Australia/ New Zealand South Central Asia NorthAfrica SouthAfrica CentralAmerica Western Europe Europe NorthAmerica

3. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria COLORECTAL CANCER U.S. age-adjusted death rate* 1930 – 1997, male 80 70 60 50 40 30 20 10 0 Year Lung & Bronchus Prostate Colon & Rectum 19301940195019601970198019901997 Rate per 100,000 Male Population Estimated incidence (% of all cancers in men): Prostate=31%; Lung & Bronchus=14%; Colon and rectum=10% *Adjusted to the age distribution of the 1970 census population. Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36.

4. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria COLORECTAL CANCER U.S. age-adjusted death rate* 1930-1997,female Year 80 70 60 50 40 30 20 10 0 Lung & Bronchus Colon & Rectum Breast 19301940195019601970198019901997 Rate per 100,000 Female Population Estimated 2001 incidence (% of all cancers in women): Breast=31%; Lung=13%; Colon and rectum=11% *Adjusted to the age distribution of the 1970 census population. Greenlee RT, et al. CA Cancer J Clin. 2001;51:15-36.

5. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria –Age  40 –Family history –Familial adenomatous polyposis syndromes (FAP) –Inherited colorectal cancer in Ashkenazi Jews –Juvenile polyposis –Peutz-Jeghers syndrome –Hereditary nonpolyposis colorectal cancer (HNPCC) Lynch I syndrome Lynch II syndrome –Inflammatory bowel disease –Colorectal cancer –Pelvic irradiation –Neoplastic colorectal polyps –Granulomatous colitis Risk factors COLORECTAL CANCER Risk factors General:Genetic:Pre-existing: Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1216-1271.

6. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Prevention COLORECTAL CANCER Prevention Although no dietary element has proven benefits in cancer prevention, there is some data indicating that the following may be helpful: Low-fat, high-fiber diet Calcium supplements Aspirin or NSAIDs Hamilton JM, Grem JI. Current Cancer Therapeutics. 3rd ed. 1998;156.

7. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Screening (average risk) COLORECTAL CANCER Screening (average risk) Men and women age  50, no known risk factors should undergo one of the following: Fecal occult blood test (FOBT) annually + flexible sigmoidoscopy every 5 years; Annual FOBT; Flexible sigmoidoscopy every 5 years; or Colonoscopy every 10 years; or Double-contrast barium enema every 5 years. Smith RA, et al. CA cancer J Clin. 2001;51:38-75.

8. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Screening (high risk) I COLORECTAL CANCER Screening (high risk) I Age 40, if first-degree relatives had colorectal cancer or adenomatous polyp –Same diagnostic options as average risk patient History of FAP –Consider genetic counseling and testing –Flexible sigmoidoscopy every year starting at puberty History of HNPCC –Consider genetic counseling and testing –Exam of entire colon every 1–2 years, starting between the ages of 20–39, and every year after age 40 Winawer SJ, et al. Gastroenterology. 1997;112:594-642.

9. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Screening (high risk) II COLORECTAL CANCER Screening (high risk) II Personal history of one of the following: Adenomatous polyps –Colon examination 3 years after initial exam; if normal at first follow-up, then every 5 years Inflammatory bowel disease –Surveillance colonoscopy every 1–2 years beginning 8 years after disease onset in patients with pancolitis, or after 15 years in those with colitis of left colon only Winawer SJ, et al. Gastroenterology. 1997;112:594-642.

10. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Symptoms and progression COLORECTAL CANCER Symptoms and progression Early stages No symptoms Abdominal pain Flatulence Minor changes in bowel movements Rectal bleeding Anemia Constipation or diarrhea Abdominal pain (colicky pain) Obstructive symptoms (nausea/vomiting) Late-stage right-sided colon Vague abdominal aching Anemia (iron loss by chronic microscopic bleeding) Weakness Weight loss Change in bowel movements Rectal fullness Urgency Bleeding Tenesmus Pelvic pain (later stage) Late-stage rectum Late-stage left-sided colon

11. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Pretreatment evaluation COLORECTAL CANCER Pretreatment evaluation HistoryHistory –Including familial history of CRC/polyps/other cancers Physical ExaminationPhysical Examination –Digital examination of the rectum –Hepatomegaly/ascites/lymphadenopathies –In women: breast/ovarian abnormalities Laboratory DataLaboratory Data –Blood count, liver chemistry Gastrointestinal ExaminationGastrointestinal Examination –Chest X-ray –Full colonoscopy –Abdominal pelvic CT scan or ultrasound –Serum CEA levels

12. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Sigmoidoscopy RECTAL CANCER Sigmoidoscopy

13. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria COLON CANCER Flexible sigmoidoscopy

14. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Diagnosis COLORECTAL CANCER Diagnosis Hamilton IM, Grem JL. Current Cancer Therapeutics. 3rd ed. 1998;157. Stage I15% Stage II20%–30% Stage III30%–40% Stage IV20%–25% Disease Stage at Time of Diagnosis

15. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria COLORECTAL CANCER Prognostic factors (after surgery) Stage Invasion of blood/lymphatic vessels Number of involved local lymph nodes Penetration or perforation of bowel wall Rosenbaum EH, Dollinger M. Everyone’s Guide to Understanding Cancer. 3rd ed. 1997;430-449.

16. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria COLORECTAL CANCER Prognostic factors (rectal cancer) Additional unfavorable factors in rectal cancer: Invasion or adherence of tumor to other parts of the pelvis or adjacent tissues Deeply ulcerated tumor Tumor encircles rectal wall Tumor is >6 cm Rosenbaum EH, Dollinger M. Everyone’s Guide to Understanding Cancer. 3rd ed. 1997;430-449.

17. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Prognostic factors (colon cancer) COLORECTAL CANCER Prognostic factors (colon cancer) Unfavorable factors in colon cancer: Obstruction of large bowel or rectum Pelvic/abdominal node involvement Invasion of veins/lymphatic vessels of bowel Tumor cells poorly differentiated Abnormal chromosome pattern of tumor cells Higher serum CEA levels post-surgery Tumor cell DNA abnormality Rosenbaum EH, Dollinger M. Everyone’s Guide to Understanding Cancer. 3rd ed. 1997;430-449.

18. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Histologic type: Pedunculated adenoma COLORECTAL ADENOMA Histologic type: Pedunculated adenoma AdenocarcinomaAdenomatousepithelium Normal colonic mucosaMuscularismucosae SubmucosaMuscularispropria Subserosal connective tissue Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1216-1271.

19. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Histologic type: Sessile adenoma COLORECTAL ADENOMA Histologic type: Sessile adenoma AdenocarcinomaAdenomatousepithelium Normal colonic mucosaMuscularismucosae SubmucosaMuscularispropria Subserosal connective tissue Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1216-1271.

20. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Anatomic segments and vascular supply COLON Anatomic segments and vascular supply RIGHTLEFT Ascending colon Descendin g colon Hepatic flexure Transverse colon Splenic flexure Sigmoid colon Cecum Sup. hemorrhoi dal a. and v. Sigmoid a. Ileocolic a. R. colic a. Mid colic a. Sup. mes a. and v. Inf. mes. v. L. colic a. Inf. mes. a. Aort a small intesti ne Internal pudendal a. Middle hemorrhoidal a. Inferior hemorrhoidal a. Rectum Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1216-1271.

21. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Anatomy RECTUM Anatomy Left upper valve of Houston Right middle valve of Houston Peritoneum Left lower valve of Houston Anal verge AmpullaofRectum 2 7 11 15 upper 1/3 middle 1/3 lower 1/3 PortionofRectum cm from anal verge Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1271-1319.

22. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Histology of colon COLORECTAL CANCER Histology of colon Mucosa Muscularis mucosae Submucosa Muscularis propria SubserosaSerosa Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1155.

23. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria WHO histologic classification of malignant primary tumors COLORECTAL CANCER WHO histologic classification of malignant primary tumors Epithelial Tumors:Epithelial Tumors: –Adenoca.: 90-95%  Mucinous adenoca.  Signet-ring cell ca. –Squamous cell ca. –Adenosquamous ca. –Undifferentiated ca. –Unclassified ca. Carcinoid Tumors:Carcinoid Tumors: rare Nonepithelial Tumors:Nonepithelial Tumors: –Sarcoma (leiomyosarcoma and others) –Hematopoietic and lymphoid neoplasms Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1150,1153.

24. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Staging systems COLORECTAL CANCER Staging systems 1932Dukes 1954Astler & Coller 1975Gastrointestinal Tumor Study Group (GITSG) 1978Gunderson & Sosin (Modified Astler & Coller) 1987AJCC/UICC Skibber JM, et al. Cancer: Principles & Practice of Oncology. 6th ed. 2001;1216-1271.

25. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Predictive factors for malignant transformation of pre-existing adenomas COLORECTAL CANCER Predictive factors for malignant transformation of pre-existing adenomas *Relative Risk. Hamilton JM, Grem JL. Current Cancer Therapeutics. 3rd ed. 1998;156. O’Brien MJ, et al. Gastroenterology. 1990;98:370-379. Number: Dysplasia: Histology:Morphology:Size: Villous:+++ Tubular villous:++ Tubular:+ Sessile > pedunculated < 1 cm: Risk = 1%  1 –  2 cm: Risk = 5–10% > 2 cm: Risk = 20–50% RR* increased with the number of adenomas Risk of malignant transformation: — Low grade: 6% — High grade: 35%

26. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TNM classification: definition of T (primary) COLORECTAL CANCER TNM classification: definition of T (primary) TisT 1 T 2 T 3 T 4 Mucosa Muscularis mucosa Submucosa Muscularis propria SubserosaSerosa Extension to an adjacent organ

27. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TNM classification: Primary tumor COLORECTAL CANCER TNM classification: Primary tumor TX TXPrimary tumor cannot be assessed T0 T0No evidence of primary tumor Tis TisCarcinoma in situ: intraepithelial or invasion of lamina propria* T1 T1Tumor invades submucosa T2 T2Tumor invades muscularis propria AJCC ® Cancer Staging Manual, 5 th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania. * Note: Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.

28. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TNM classification: Primry tumor II COLORECTAL CANCER TNM classification: Primry tumor II T3 T3Tumor invades into the subserosa, or into non-peritonealized pericolic or perirectal tissues T4 T4Tumor directly invades other organs or structures, and/or perforates visceral peritoneum* AJCC ® Cancer Staging Manual, 5 th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania. * Note: Direct invasion in T4 includes invasion of other segments of colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum.

29. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Regional lymph nodes (N) Distant metastases (M) TNM classification: N (nodes) and M (metastases) COLORECTAL CANCER TNM classification: N (nodes) and M (metastases) NX NXRegional nodes cannot be assessed N0 N0No regional lymph node metastases N1 N1Metastasis in 1 to 3 regional lymph nodes N2 N2Metastasis in 4 or more regional lymph nodes MX MXDistant metastasis cannot be assessed M0 M0No distant metastasis M1 M1Distant metastasis AJCC ® Cancer Staging Manual, 5 th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania.

30. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Correlation between TNM and Dukes staging systems COLORECTAL CANCER Correlation between TNM and Dukes staging systems AJCC/ UICCDukes* AJCC/ UICCDukes* Stage 0 Stage 0TisN0M0— Stage I Stage IT1N0M0A T2N0M0— Stage II Stage IIT3N0M0B T4N0M0— Stage III Stage IIIAny TN1M0C Any TN2M0— Stage IV Stage IVAny TAny NM1— AJCC ® Cancer Staging Manual, 5 th edition (1997) published by Lippincott-Raven Publishers, Philadelphia, Pennsylvania. * Dukes B is a composite of better (T3 N0 M0) and worse (T4 N0 M0) prognostic groups, as is Dukes C (any T N1 M0 and any T N2 M0).

31. Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Sites and frequency of distant metastases COLORECTAL CANCER Sites and frequency of distant metastases Kemeny N, Seiter K. Handbook of chemotherapy in clinical oncology. SCI ed.1993;589-594. Liver Liver38-60% Abdominal lymph nodes Abdominal lymph nodes39% Lung Lung38% Peritoneum Peritoneum28% Ovary Ovary18% Adrenal glands Adrenal glands14% Pleura Pleura11% Bone Bone10% Brain Brain8%