ADVANCES IN COLORECTAL CANCERS IS THERE HOPE? Dr Lim Hwee Yong Medical Oncologist

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1 ADVANCES IN COLORECTAL CANCERS IS THERE HOPE? Dr Lim Hwee Yong Medical Oncologist

2 CRC: Epidemiology in 2012 Third most common cancer diagnosis in US [1] Estimated 143,460 new cases in 2012; 1:1 male:female ratio [2] At diagnosis, 39% localized (stage 0-II), 37% regional (stage III), 20% metastatic (stage IV) [3] Steady decrease in ageadjusted incidence rates of distal colon, proximal colon, and rectal cancers in [4] Third leading cause of cancer deaths in 2011 (estimated 49,380 deaths) [1] Race/Ethnicity Death Rates in 2008, per 100,000 [3] All races 16.4 White 15.8 African American 23.0 Asian/Pacific Islander 11.5 American Indian/ Alaska Native 19.1 Hispanic American Cancer Society. Colorectal cancer facts & figures Siegel R, et al. CA Cancer J Clin. 2012;62: SEER. Stat fact sheets: colon and rectum. 4. Cheng L, et al. Am Clin Oncol. 2011;34:

3 Introduction Colorectal cancer is the most common cancer in Singapore According to the 5yearly report ( ) from the Singapore Cancer Registry, it has the highest incidence amongst malignancies in male & is second only to breast cancer in female

4 Introduction 4

5 Introduction 5

6 Introduction 6

7 Major Risk Factors for CRC Factors That Increase Risk Heredity and Medical History Family history 1 first-degree relative More than 1 relative Relative with diagnosis before 45 yrs of age Inflammatory bowel disease Crohn s disease Ulcerative colitis (colon) * Relative risk compares risk of disease in people with exposure to risk of people without exposure. American Cancer Society. Colorectal cancer facts & figures Relative Risk* Diabetes 1.2 Smoking 1.2 Factors that decrease risk are physical activity (in colon cancer), calcium, and consumption of milk

8 Impact of Personal and Family History in CRC 20% of patients with CRC have close relative with CRC 5% of CRC cases are associated with genetic syndrome Lynch syndrome (HNPCC) most common, accounting for 2% to 4% of all cases Higher risk of other cancers (eg, endometrial, ovarian, pancreatic) Familial adenomatous polyposis, second most common and associated with nearly 100% lifetime risk of CRC without intervention BRCA associated with increased risk of CRC Previous history of localized CRC associated with increased risk of new CRC tumors American Cancer Society. Colorectal cancer facts & figures

9 Screening

10 Young Colorectal CA

11 FAP AD. Germline mutation of tumour suppressor gene APC in short arm of chromosome 5 1% of all CRCs; Prevalence 1: and penetrance is 100% Characterized by multiple polyps(> 100, less in AAPC) appearing during childhood, symptomatic by 16 yrs. 90% devt Ca at 45 years. Variants include Turcot s (AR), Gardner s (AD) and attenuated adenomatous polyposis coli (AAPC) Some patients have congenital hypertrophy of the retinal pigment epithelium (CHRPE), the presence of which may provide a clue toward the diagnosis In addition to colorectal adenocarcinoma, patients with FAP are at risk for several extracolonic malignancies including: Duodenal ampullary carcinoma, Follicular or papillary thyroid cancer, Childhood hepatoblastoma,gastric carcinoma, CNS tumors (mostly medulloblastomas) Genetic testing: should be done on a known affected family member first to determine if there is a detectable mutation

12 Screening/ Mx in FAP Families FAP index pt APC mutation +ve APC testing in relatives +ve -ve Prophylactic total colectomy (10-19yo) No surg/ surveillance needed APC mutation -ve No need for APC testing in relatives Annual colonoscopic surveillance If polyps +ve, total colectomy

13 HNPCC AD. 1-5% of all CRCs. Gene mutation affecting DNA mismatch repair, commonly hmsh2 and hmlh1 (95% of HNPCC) confers at least a 25% risk of developing colorectal cancer by age 50 and a 70% to 80% risk by age 70 Amsterdam Criteria: a) >/=3 relatives with colorectal cancer (1 of whom is the first-degree relative of the other 2) b) >/ 2 generations affected c) >/ 1 of those affected diagnosed at age <50 Colonoscopic surveillance biannually from 20yo (or 5yr earlier than the youngest case of CRC in family), annually from 40yo

14 Primary tumor (T)* Tis T1 T2 T3 T4 Carcinoma in situ; intraepithelial (within glandular basement membrane) or invasion of lamina propria (intramucosal) Tumor invades submucosa Tumor invades muscularis propria Tumor invades through the muscularis propria into the subserosa, or into non-peritonealized pericolic or perirectal tissues Tumor directly invades other organs or structures, and/or perforates visceral peritoneum Regional lymph node (N) NX Regional nodes cannot be assessed N0 No regional nodal metastases N1 Metastasis in 1 to 3 regional lymph nodes N2 Metastasis in 4 or more regional lymph nodes Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage Groupings Stage 0 Tis N0 M0 Stage I T1-2 N0 M0 Stage IIA T3 N0 M0 Stage IIB T4 N0 M0 Stage IIIA T1-2 N1 M0 Stage IIIB T3-4 N1 M0 Stage IIIC Any T N2 M0 Stage IV Any T Any N M1

15 TNM staging Dukes staging NEED >= 12 LYMPH NODES

16 Survival SEER Stage 5 year survival I 93% II A B 85% 72% III A 83% B 64% C 44% IV 8%

17 Adjuvant Treatment FU/LEV 5FU/LV 5FU/LV = 5FU/LEV 6 mos = 12 mos HDLV = LDLV Weekly = Monthly Oral 5FU = BIV 5FU CIV 5FU = BIV 5FU FOLFOX > 5FU/LV Bevacizumab not useful in adj Rx Cetuximab not useful in adj Rx

18 Adjuvant Treatment To remember 5FU Capecitabine (Oral 5FU prodrug) Combination with Oxaliplatin Stage III High risk Stage II T4, perforation, obstruction, perineural invasion, lymphovascular invasion Inadequate Lymph nodes sampling, poorly differentiated histology

19 ADJUVANT CHEMOTHERAPY Adjuvant online

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21 Rectal cancer

22 Epidemiology 2008: 40,740 new cases (23,490 men; 17,250 women) Lumped with colon cancer as the 3 rd most common cancer in the US (112,340 new cases in US in 2007)

23 PRE-OP STAGING EUS v. MRI Both are 94% sensitive to determine invasion into muscularis Specificity: EUS 86%, MRI 69% Considered equal for evaluating lymph nodes, but understages 1/5 of patients Mercury trial - Radiology Apr;243(1): Epub 2007 Feb % CI to +/- 0.5mm

24 DEFINING THE RECTUM

25 WHY IS THE RECTUM SO SPECIAL? Sphinter: Preservation = QOL Close proximity to other organs (hard to get wide margins = higher local relapse) absence of serosa fixed in space

26 Rectal cancer Different surgical approach APR, LAR Total Mesorectal resection Chemo-radiation therapy (usually neoadjuvant) T3, T4, node positive.

27 METASTATIC DISEASES

28 HOW CANCER GROWS

29 Paradigm Shift Breakthroughs in molecular biology Identification of distinctive molecular signatures Allows targeting of these molecular signatures Era of rational therapy (as opposed to empiric)

30 Systemic anti-cancer therapy Cytotoxic therapy, e.g. 5 Fluorouriacil, Oxaliplatin Hormonal therapy, e.g. tamoxifen Immunological therapy, e.g. interferon Targeted therapy, e.g. imatinib (Glivec)

31 Treatment approach Liver only/ Lung only Resectable Neoadjuvant with Cytotoxic chemorx + Biologics Surgery Adjuvant ChemoRx * M 1 Abdominal/ peritoneal disease/ Multifocal disease/ Not resectable Unresectable Palliative ChemoRx Surgery Chemotherapy adjuvant intent

32 Treatment - Metastatic Metastatectomy? Isolated mets? Curable? Neoadjuvant chemotx? 5FU/LV Oxaliplatin Irinotecan Cetuximab Panitumumab Bevacizumab Aflibercept? (VEGF trap)

33 TARGETED THERAPY

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35 Monoclonal antibodies (MABs)

36 Tyrosine kinase inhibitors (TKIs)

37 EGFR-mediated pathway MABs Trastuzumab (HER2) Cetuximab (EGFR) Panitumumab (EGFR) TKIs Erlotinib (EGFR) Gefitinib (EGFR) Lapatinib (EGFR/HER2)

38 CETUXIMAB-INDUCED SKIN RASH Acneiform rashes

39 VEGFR-mediated pathways MAB Bevacizumab (VEGF) Multitargeted TKIs Sunitinib (PDGF, C- KIT, FLT3, VEGFR) Sorafinib (PDGF, C- KIT, FLT3, VEGFR, RAF) Thalidomide

40 Considerations Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) Functional status ECOG or KPS

41 Treatment Stage I: Resection. (T1-2, N0, M0) Stage II: Resection. Consider adjuvant chemotherapy? (T3-4, N0, M0) Stage III: Surgery plus adjuvant chemotherapy. (any T, N1-2, M0) Stage IV: Chemotherapy. Surgery in selected cases (Any T, any N, M1)

42 Surveillance Hx/ PE every 3m for 2y; then every 6m for total 5y CEA every 3m for 2y; then every 6m for total 5y (for T2 or greater) CT T/A/P yearly for up to 5y for pt at high risk of recurrence For M1 disease: CT every 3-6m x 2y, then every 6-12m for total 5y Colonoscopy in 1y ; if abnormal, repeat in 1y, if advanced adenoma repeat in 3y and if normal, repeat in 5y

43 Questions 45 yo man is brought from his job on a constuction site to the emergency department with acute right sided abdominal pain, nausea and vomiting. CT scans shows inflamed area in the right lower abdominal quadrant. Intraoperatively, he is found to have an obstructing lesion in the cecum. Frozen section confirms high garde adenocarcinoma and right hemi-colectomy and lymph node dissection are done. Biopsy specimens confirms Stage III T3 N2 colon cancer with 5 of lymph nodes positive for metastatic disease. Post operative CT scans of Thorax, Abdomen and Pelvis and complete colonoscopy show no synchronous lesions or distant metastases.

44 Questions Which of the following is the most appropriate post operative management A) Chemotherapy B) Chemotherapy and radiation therapy C) Radiation therapy D) Observation

45 Questions If the patient has node negative disease and the final staging is T3 N0 M0 disease, Which of the following is the most appropriate post operative management A) Chemotherapy B) Chemotherapy and radiation therapy C) Radiation therapy D) Observation

46 Questions A 56 year old woman undergoes initial screening colonoscopy. An abnormality is found 10 cm from the anal verge. Biopsy specimens confirm the diagnosis of a moderately differentiated adenocarcinoma. MRI pelvis shows that the tumor has extended into the perirectal fat, but no lymphadenopathy is noted. Chest radiograph and CT scans of the Thorax, Abdomen shows no metastatic disease.

47 Questions Which of the following is the most appropriate treatment at this time: A) Neo-adjuvant Chemoradiation followed by surgical resection B) Surgery and followed by adjuvant chemotherapy C) Radiation therapy alone D) Chemotherapy alone E) Surgical resection postoperative radiation alone

48 Thank You