Multidisciplinary approach to colorectal cancer treatment

1. Multidisciplinary approach to colorectal cancer treatment Łukasz Kwinta

2. Background

3. Background • Colorectal cancer is the second most commonly diagnosed cancer world wide in women, third in men • Third leading cause of cancer deaths in the U.S. • The lifetime incidence for patients at average risk is 5 percent, with 90 percent of cases occurring after age 50. • Lifetime probability: 1 in 20 (men),1 in 22 (women) • Both the incidence of and mortality rates from CRC have been declining in the US

4. U.S. Cancer statistics, 2014:Estimated New Cases & Deaths

5. Pathology • Adenocarcinoma (90-95% of CRC) Special types within adenoca group: • Mucinousadenocarcinoma (10% of adenoca) • Large quantities of extracellular mucus • Tendency to spread within the peritoneum • Lower sensitivity for PET-CT • Signet-ring cell carcinoma (1% of adenoca) • Large quantities of intracellular mucinous • Probably more aggressive • Other • Squamous cell (anal cancer) • Small cell, carcinoid tumors, adenosquamous, GIST, sarcomas, lymphomas etc.

6. Pathology - grading • Histologic grade • G1 – well differentiated • G2 – moderately differentiated • G3 – poorly differentiated • Correlates with aggressiveness of the disease

7. Risk Factors For Colorectal Cancer • Increasing age (highest in people older than 85 years) • Diet: red meet, highly processed meet • High fat, high protein, low fiber diet • High consumption of alcohol • Cigarette smoking • Obesity • Lack of physical activity • DM type II or insulin ressistance

8. Who is at high risk? • Personal history of: • Colorectal cancer • Adenomatous polyps • Inflammatory bowel disease (UC or Crohn’s) • Family History of: • Colorectal cancer • Polyps • Hereditary Colorectal Cancer Syndromes: • Familial adenomatous polyposis (FAP) • Hereditary non-polyposis colon cancer (HNPCC)

9. Pathogenesis • Inherited and acquired genetic defects (Adenomas to dysplasia and carcinoma) • Progression takes at least 10 years on average • Most colorectal polyps are adenomatous(2/3) • The risk of CRC increases with adenoma size, number, and histology (villous adenomas>tubular adenomas) • Removal of adenomatous polyps prevents cancer

10. Pathogenesis

11. Sporadic Cancer • All cancer arises from changes in genes…. • But NOT all cancer is inherited • Most CRC is sporadic~75 – 80% (due to acquired mutations throughout a person’s lifetime) • Sporadic cancer generally has a later onset

12. Proportion of Hereditary CRC Familial ~15% Hereditary ~5% Lynch syndrome ~ 2-5% FAP ~ <1% Sporadic 80%

13. Compared to sporadic cancer people with hereditary cancer have… • A higher risk of developing cancer • A younger age of onset of cancer • Generally < 50 years of age • Multiple primary cancers • Generally have a family history of cancer

14. Hereditary Colorectal Cancer Two common syndromes: • Lynch syndrome • Also known as Hereditary Non Polyposis Colorectal Cancer or HNPCC • ~2 - 5% of colorectal cancer • Prevalence of 1 in 200 - 2,000 • Familial Adenomatous Polyposis (FAP) • <1% of colorectal cancer • Prevalence of 1 in 8,000 – 14,000 • Autosomal dominant inheritance

15. Lynch syndrome (HNPCC) • Lynch syndrome is genetically heterogeneous • Clinical testing available for 4 genes: MLH1 & MSH2 (most common), MSH6 & PMS2 • Characterized by: • Earlier onset than sporadic cancer • More aggressive, proximal, right sided tumours • Risk for extra-colonic tumours • Distinct tumour pathology

16. Cancers susceptibility in Lynch Syndrome

17. Familial Adenomatous Polyposis • Chromosome 5, APC gene • Characterized by: • Early onset • >100 adenomatous polyps • Variant form: • Attenuated FAP may occur with >10 but <100 polyps.

18. Familial Adenomatous Polyposis • Colorectal adenomatous polyps begin to appear at an average age of 16 years (range 7-36 years) • Average age at diagnosis: 34-43 years, when >95% have polyps

19. Familial Adenomatous Polyposis • ~50-90% develop small bowel polyps • lifetime risk of small bowel malignancy is 4-12% • ~50% develop gastric polyps • ~10% gastric cancer • ~10% develop desmoid tumours

20. Familial Adenomatous Polyposis

21. Screening

22. Colonoscopy • Colonoscopy permits endoscopic evaluation of the entire colorectum. • Dietary restrictions and full cathartic preparation are required prior to the procedure. • In contrast to other endorsed screening options, therapeutic polypectomy can be completed during the baseline procedure. • Sigmodoscopy – max to splenic flexure (60 cm)

24. Screening tests - imaging • Double contrast Barium Enema (DCBE): detects only 50% of adenomas larger than1.0 cm and 39% of allpolyps. Retrospective studies have found that DCBE may miss 15-22% of CRC • CT colonography (CTC) – „virtualcolonoskopy” • Abnormal results need to be followed up by colonoscopy for excision and tissue diagnosis, or, for smaller lesions, surveillance with CTC • Flat adenomas may have greater malignant potential than polypoid lesions and are more likely to be missed on CTC than colonoscopy

25. Screening tests – stool based • FOBT : guaiac method • It is not a good test for the detection of polyps, which usually do not bleed. • 3 consecutive stool specimens • Fecal immunochemical test (FIT): • Sensitivities of FIT is 2-3x higher than gFOBT • more specific than guaiac tests because they respond only to human globin and do not detect foods with peroxidase activity. • fewer stool samples (1-2); automated analysis.  • Stool DNA: gene amplification technique • detection of low frequency mutations with increased sensitivity for advanced adenomas, with testing for hemoglobin and for patterns of DNA methylation • More sensitive than FIT. More false positives (up to 10%).

26. Guidelines-Average Risk: American Cancer Society 2008 Begin Screening at Age 50; discontinue when the individual's estimated life expectancy is less than 10 years.

27. Guidelines-USPTF (US Preventive Services Task Force) 2008 • Three screening options for adults age 50 to 75 years: based on systematic literature review and a simulation decision model • Annual sensitive gFOBT or FIT • Flexible sigmoidoscopy every five years, with sensitive FOBT every three years • Colonoscopy every 10 years • The task force found insufficient evidence of harms and benefit for DCBE, CTC or stool DNA testing.

28. Guidelines • American College of Gastroenterology 2008- guidelines recommend a "preferred" strategy, prioritizing options listed in the ACS-MSTF guidelines • colonoscopy as the preferred screening/prevention test • FIT as the preferred screening/detection test for patients who decline cancer prevention tests • Additionally, the ACG recommends initiating screening at age 45, rather than 50, for African Americans • National Comprehensive Cancer Network consensus guidelines2013 • colonoscopy every 10 years, when available, as the preferred screening strategy. • alternatives are annual stool testing with guaiac or immunochemical reagent or sigmoidoscopy every five years with or without annual stool testing.

29. Personal History:Surveillance after Initial Colonoscopy

30. Personal/Genetic History:

31. Colonoscopy at age 40 years • Family history contributes to 30% to 35% of all colorectal cancer cases. • Several hereditary cancer syndromes (eg. familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer syndrome) are associated with significantly increased risks for colorectal neoplasia and other malignancies. • Nonsyndromicfamily histories are also associated with increased colorectal cancer risk. • The 2012 American College of Physicians Guidance Statement on colorectal cancer screening recommends initiation of screening in high-risk patients at age 40 years, OR 10 years younger than the earliest colon cancer diagnosis in the family, whichever is earlier. • In the absence of gastrointestinal symptoms, colonoscopy now is not indicated as colon cancer screening can be postponed until age 40 years.

32. Diagnosis

33. Anatomical distribution

34. Clinical manifestations • Abdominal pain • Blood in stool • Melena (menatochezia) • Occult blood in stool • Microcytic anemia • Change in bowel habits • Palpable mass • Obstructive symptoms • Nausea, vomiting • Small-caliber (pencil-size) stools • Fatigue • Anorexia

35. Diagnosis Histopatology • Tissue material obtained in colonoscopy • Biopsy of metastatic lesion • Cytology (e.g. ascites fluid)

36. Diagnosis Imaging • CT/MRI - chest, abdoment, pelvis • US - abdomen, pelvis • TRUS – rectal cancer • X-ray chest • Bone scan • PET-CT

37. Diagnosis Laboratory workup – tumor markers • CEA – carcinoembryonic antigen • Membrane glycoprotein • Normal level in adults – up to 5 ng/ml (higher in smokers) • Elevation of CEA depending on cancer stage: • Stage I- 3% • Stage II- 25% • Stage III - 45% • Stage IV - 65% • Elevation occurs in other malignancies and some benign conditions • Other markers, e.g. Ca 19-9

38. Staging - TNM

39. Staging

40. TNM Staging (AJCC-7)

41. Staging and survival

42. Treatment

43. Non-metastatic colon cancer (I-III)

44. Colorectal ca managemement - overview Diagnosis & Staging Colon Rectum Neoadjuvant CRTH Surgery Surgery Adjuvant CTH Follow-up

45. Cancer of the Colon Liver Flexure: RHCE

46. Resection of Transverse Colon

47. Cancer of Descending Colon. LHCE

48. Cancer of Sigmoid Colon. Resection

49. Colostomy

50. Treatment of Colon Cancer (local and locoregional spread) No adjuvant chemotherapy T1-T3N0M0 SURVEILLANCE T4N0M0, no high-risk features No adjuvant chemotherapy T4N0M0 high-risk features:grade 3-4, lymphovascular invasion, bowel obstruction, <12 lymph nodes examined, perforation, +margins Consider adjuvant chemotherapy Adjuvamt chemotherapy (6 months) T any N1-3M0