Medical oncologic management of Colorectal cancer-1-1.pptx

Surgical note

1. Medical Management of C olorectal Cancer By Yitayal Lebeza R-4 Moderators Dr Zerubabel - Consultant Clinical Oncologist Dr Zeynedin - Consultant General Surgeon 1

2. Outline Epidemiology Risk factors P revention and screening Pathogenesis Clinical presentation and Diagnosis Management Follow up Reference’s 2

3. Objective To better understand non- operative management of colorectal cancer 3

4. Epidemiology CRC is the most common malignancy of the GI tract and 3 rd most common tumor Over 130,000 new cases and more than 50,000 deaths annually in the US. Incidence is similar in men and women with life time incidence is 6% Ethiopia, colorectal cancer is the third most common cancer with an incidence of 8/100,000 person-years Incidence decreasing in those over 50 yrs. of age ( screening, early detection and improved medical and surgical care). People younger than 50 have been experiencing an increase in incidence and worse mortality. 4

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6. Risk factors, prevention and screening Modifiable risk factors Smoking Excessive alcohol consumption Obesity Increased consumption of read meat Decreased intake of fruits and vegetables Physical inactivity Non modifiable risk factors Age ( older age >50) Family history of colorectal cancer or colorectal polyps Inflammatory bowel disease Certain genetic syndromes Radiation ureterosigmoidostomy 6

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8. Pathogenesis Carcinogenesis in the colon is a complex and multistep process (Progressive accumulation of genetic changes) Several categories of genes are involved Disruption of the fine balance between oncogenes and tumor suppressor genes as well as abnormalities of DNA mismatch repair genes >> growth advantage Adenoma- carcinoma sequence ( most CRCs arise from a pre-existing adenomatous polyp) 8

9. Three major Genetic pathways The loss of heterozygosity (LOH, chromosomal instability) pathway The microsatellite instability (MSI) pathway The CpG island methylation(CIMP; serrated methylated) pathway 9

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11. Inherited Colorectal Carcinoma Familial adenomatous polyposis Autosomal dominant Mutation in the APC gene located on chromosome 5q. APC mutuation testing is positive in 75% of cases. Upto 25% present without other affected family members. Risk of developing CRC 100% by age 50 years. 11

12. Attenuated Familial adenomatous polyposis Variant of FAP, characterized by fewer polyps (10-100) located mainly in the right colon. Mutuations in MYH and APC gene(30 %) are present. Around 50 % of them develop colorectal cancer. Genetic testing recommended. 12

13. Hereditary non polyposis colon cancer Accounts for 1-3 % of colon cancers. Errors in mismatch repair ( MSI) Inherited in autosomal dominant pattern Develop CRC at an early age ( average 40-45 yrs ) 70% of affected individuals will develop CRC. Appear in the proximal colon more often than sporadic one’s. Risk of synchronous or metachronus CRC=40% Have a better prognosis Affected families are identified with Amsterdam criteria. 13

14. Familial colorectal cancer 10-15% of patients with CRC. Life time risk of developing colorectal cancer No family hx =6% One first degree relative=12% Two first degree relatives =35% 14

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17. Macroscopic Annular Obstructive Transverse and descending colon Tubular (diffusely infiltrating) More often in the rectosigmoid Commonly associated with ulcerative colitis Ulcer Most common Cauliflower ( polypoid ) Often a low grade malignancy Usually in the ascending colon 17

18. Clinical Presentation History Asymptomatic Symptoms of CRC are non specific and generally develop when locally advanced Change in bowel habits and rectal bleeding Abdominal pain, bloating Bleeding tenesmus and pain Unexplained anemia Weight loss and poor appetite 20% present as an emergency 20% present as a stage IV disease 18

19. Physical examination General examination- nutritional status and performance, signs of anemia Lymphadenopathy supraclavicular and inguinal Abdomen palpable mass, ascites, hepatomegaly, signs of peritonitis Pelvic examination for women with anterior lesion DRE palpable mass or blood Extra intestinal manifestations 19

20. Unusual presentations Fistula formation into adjacent organs Abscess formation Septicemia Bleeding- better prognosis because of early detection Obstruction/perforation-worse prognosis 20

21. Diagnosis Investigation s CBC, BG RH, OFT, Serum electrolyte, albumin Fecal occult blood, CEA Endoscopy Anoscopy Sigmoidoscopy- -rigid sigmoidoscopy is mandatory for distal left sided lesions. Flexible fiber optic sigmoidoscopy Colonoscopy with biopsy Radiology Abdominal and endorectal U/S Barium enema CT MRI IVP PET scanning Use of CEA in colorectal cancer Preoperative level ( > 7.5 ng/ml) poor prognosis) If postoperative level does not fall, indicate either incomplete resection or occult mets elsewhere Increased level postoperatively- recurrence or secondaries 21

22. Abdominopelvic U/S and CT Regional tumor extension Lymphatic and distant metastasis Tumor related complications, like perforation and fistula formation The accuracy of CT in determining the depth of invasion is low as compared to ERUS and MRI. CT Scan 22

23. Endorectal U/S Superior to CT and MRI in T staging. Less useful in predicting the status of perirectal lymph nodes. Endoscopic U/S staging of rectal tumors 23

24. MRI Superior to ERUS in identifying involved perirectal nodes based on characteristics other than size (accuracy=95%) Pelvic side wall involvement 24

25. Staging 25

26. Prognostic factors Histopathologic prognostic factors Depth of tumor invasion (pT4) Lymph node metastasis Tumor differentiation grade Venous and lymphovascular invasion Perineural invasion Tumor resection margin Clinical prognostic factors Age Emergency presentation Invasion of adjacent organs 26

27. Management of colorectal cancer Multidisciplinary team (MDT) approach Ideal for the management of patients with colorectal cancer especially in locally advanced and recurrent CRC. Involvement of multiple subspecialists MDT team is involved in Staging process Pathologic evaluation Type of surgery needed and for neoadjuvant and adjuvant therapy 27

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29. Preoperative evaluation Physiologic assessment ( performance status and nutritional status) Localization of the tumor and histopathology Proper staging and Operative plan Familial cancer syndromes ?? ( total abdominal colectomy or simple segmental resection) Baseline CEA Full colonoscopy to detect synchronous lesion Bowel preparation Thromboembolic prophylaxis Preoperative marking of stoma site Urinary catheters/stents 29

30. Treatment of colonic adenocarcinoma Stage specific therapy Stage 0 (Tis,N0,M0) polyps containing carcinoma insitu ( high grade dysplasia) carry no risk of lymphnode metastasis. Endodcopic removal ( margin should be free of dysplasia) Colonoscopy follow up If polyp is not completely removed- segmental resection 30

31. Stage I Only surgery Stage II Surgery +/- Chemo Adjuvant chemotherapy for selected stage II disease, like young patients and tumors with “ high risk ” histologic findings. Stage III disease ( Tany,N1,M0 ) Significant risk for local and systemic recurrence- need adjuvant chemotherapy 31

32. Factors that predict recurrence in stage 1 - 3 MSI/MMR deficiency (lynch syndrome) Stain all tumors for mismatch repair protiens Absent- good prognosis Don’t benefit from adjuvant chemo 20% of stage 2 tumors have absent MMR protiens Recurrence risk scores Oncotype dx, colprit , col dx Don’t predict benefit from chemo – not recommended CDX2 Predict high risk of recurrence and benefit from chemo 4% of tumors lack CDX2 protien 32

33. Adjuvant chemo 33

34. Adjuvant chemo cont’d six to eight weeks of resection Reasons for delay Late recovery inefficiencies in the healthcare system shortages of resources to deliver care patient-related issues greater levels of comorbidity, lack of social support, and lower socioeconomic status  worse overall and event-free survival (EFS ) and relapse with a delay beyond eight weeks 34

35. Chemo cont’d Duration of therapy oxaliplatin -based adjuvant therapy 3 vs 6 months 3 mn for low risk 6 mn for high risk 3mn oxaliplatin plus  capecitabine   (CAPOX) may be a better choice than oxaliplatin plus  leucovorin  and short-term infusional   fluorouracil   FOLFOX non- oxaliplatin -based regimen ( ie , a fluoropyrimidine alone), six months of adjuvant therapy Fluoropyrimidine therapy alone Short (three to six months) versus longer (9 to 12 months) duration  No benefit with prolonged treatement 35

36. Regimens Oxaliplatin based FOLFOX FLOX ( oxaliplatin plus bolus FU and LV) and XELOX ( oxaliplatin plus oral  capecitabine )  MOSAIC trial   2hr infusion LV + bolus FU + 22hr Infusion 5FU Q2wks vs FOLFOX4 5DFS + neutropenia + diarrhea + neuropathy high in FOLFOX NSABP C-07 trial three cycles of bolus weekly FU/LV (the Roswell Park [RPMI] regimen) with or without oxaliplatin (FLOX) 5DFS + diarrhea + death + neuropathy more in FLOX but similar OS XELOX vs with bolus  FU/LV More neurotoxic hand foot syndrome and thrombocytopenia 36

37. Regimens Fluoropyrimidine -based therapy In those contraindicated for oxaliplatin infusional   FU   + LV (the de Gramont regimen) favorable side effect profile for continuous infusion FU over bolus FU plus LV capecitabine Comparable DFS with IV fluoropyrimidines   Low adverse effect except hand foot syndrome UFT and S1  UFT plus LV compared with parenteral FU/LV was shown in non-Asian populations No DFS difference 37

38. MSI-H or dMMR tumors we suggest not using fluoropyrimidines alone . addition of  oxaliplatin to FU can overcome fluoropyrimidine chemoresistance are fairly compelling. One option for patients with dMMR tumors who are felt unlikely to tolerate an oxaliplatin -based regimen is to start with half-dose oxaliplatin (as was done in the FOCUS2 trial conducted in patients with metastatic disease and escalate as permitted by treatment-related toxicity. 38

39. Regional therapies The liver is the dominant site of recurrence in half of patients undergoing curative resection prophylactic portal vein infusional (PVI) therapy or hepatic intraarterial infusion of fluoropyrimidines group receiving the intraportal therapy better three-year disease-free survival (85 versus 76 percent) lower rate of distant metastases (13 versus 23 percent ) But high death rate regarding the procedure 39

40. Adjuvant radiotherapy The role of adjuvant radiation therapy (RT) in patients with resected colon cancer is poorly defined. we offer adjuvant RT to the following subgroups of patients who have estimated risk of local recurrence that is 30 percent or higher : ascending or descending colon primary with T4b disease a positive resection margin perforation/abscess  formation, a fistula at the tumor site 40

41. Stage specific therapy Stage 0 (Tis, N0,M) Villous adenoma harboring carcinoma insitu (high grade dysplasia) Local excision with 1cm margin Radical resection- for large circumferential lesions. Stage I, Localized rectal carcinoma (T1-2,N0,M0) Radical resection in all good risk patients For high risk pts and those who refuse radical surgery= local excision For small favorable sessile uT1N0 and uT2N0 rectal cancers, local recurrence rate- 20% and 40% respectively ( after local excision). 41

42. Locally advanced rectal cancer( stage II and III) Stage II: localized rectal carcinoma (T3-4,N0,M0) Preoperative chemo radiation followed by surgery ( if the radial margin is threatened, anal sphincter or other organ invasion) Postoperative radiation Stage III: Lymph node metastasis( Tany,N1,M0) Pre or postoperative chemo radiation 42

43. Neoadjuvant chemoradiotherapy and radiotherapy for rectal adenocarcinoma T3 or T4 tumor. relative indications the presence of clinically node-positive disease staged  T1/2 rectal cancer, a distal rectal tumor for which an abdominoperineal resection (APR) is thought to be necessary, and a tumor that appears to invade the mesorectal fascia RT with concurrent fluoropyrimidine chemotherapy rather than the short-course Swedish approach to RT alone 43

44. adjuvant vs neoadjuvant chemoradiotherapy German Rectal Cancer Study  assigned 823 patients with clinically staged T3/4 or node-positive Neoadjuvant RT +FU TME + 4cycle FU adjuvant treatment TME + 4cycle FU received RT boost of 5.4 Gy 5DFS 68 vs 65% OS 76vs74% Pelvic relapse rate 6 vs 13 percent NSABP protocol R-03 267 pts   Neoadjuvant Higher DFS (65 VS 53%) overall survival (75 vs 66%) No d/c in locoregional 44

45. Preoperative chemoradiotherapy versus RT   EORTC 22921 trial concurrent chemoradiotherapy vs preoperative RT alone  higher rate of pCR (14 versus 5 percent) Ten-year DFS ( 46 versus 44 percent ), overall survival (51 versus 49 percent ). grade 3 or 4 treatment-related toxicity with chemoradiotherapy  the addition of adjuvant chemotherapy did not significantly improve outcomes 45

46. Stage IV: distant metastasis (T any, N any, M1) Survival is limited Isolated hepatic or pulmonary metastasis= resection for cure Palliative procedures Radical resection to control pain, bleeding or tenesmus ( avoid highly morbid procedures) Local therapy using cautery, endocavitary radiation, or laser ablation to control bleeding and prevent obstruction. Intraluminal stents Diverting stoma Involvement of a palliative care team 46

47. Chemotherapy vs Supportive care (NCCTG) trials  FU plus  leucovorin (LV ) era, only 1.1 percent of patients were alive at five years  phase III FIRE-3 trial [FOLFIRI ] plus  bevacizumab or  cetuximab ) approximately 20 percent 5 yr survival BSC median survival is approximately five to six months 47

48. Prognosis 48

49. Reference’s 49

50. Thank You 50