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Colon Cancer Overview

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Title: Colon Cancer Overview


1
Colon Cancer
  • Sung Ho Lee, MD
  • Hematology and Medical Oncology

2
  • How common and serious is Colon Cancer ?

3
Epidemiology
  • 2nd (3rd)leading cause of cancer death in US
  • 3rd most common cause of cancer (M,F)
  • Lifetime risk of CRC 118
  • Surgery will cure 50 of all dx pts.
  • Incidence higher in well developed countries

4
  • Okay.. its common and serious
  • So Who gets Colon Cancer?

5
Risk Factors
  • Age gt90 in gt50yrs age
  • Gender F more colon, M more rectal
  • Tobacco 2.5x increased adenomas
  • Obesity
  • Dietary decrease risk with fiber, low cal, low
    animal fat diet
  • Increase risk folate VitD def, IBD(UC10X)
    Crohns(2x)
  • Decrease Risk NSAID, COX-2 inhibitor, ?take
    calcium.
  • Family Hx 1st Deg Relative 1 1.76x

  • 2 2.75x
  • True hereditary form
    only 6 of CRC

6
FAP(Familial Adenomatous polyposis)
  • ADD with 90 penetrance, with hundreds of polyps
    by adolescence
  • Germline mutation of APC gene 5q21
  • -gt increased transcription of beta-catenin
  • Risk of invasive cancer 100
  • Variants Attenuated FAP
  • Gardner (soft tissue tumor)
  • Turcot (CNS tumor)
  • Peutz-Jeghers (non-neoplastic hamartomatous
    polyps through GI tract with perioral melanin
    pigmentation)

7
HNPCC (Lynch Syndrome)
  • ADD, Rt sided, Mucinous or poorly diff,
    synchronous/metachronous tumor
  • Lifetime risk 75
  • Lynch II (extracolonic) endometrium, ovary,
    stomach, GU, SI, hepatobiliary
  • Amsterdam Criteria (3,2,1,0)
  • 3 family member(1 1st deg), over 2
    generation, 1 diagnosed before 50yrs. Not FAP(0)
  • Germline mutation in DNA mismatch repair gene
  • hMSH2, hMLH1, hPMS1, hPMS2, resulting in
    MSI(microsatellite instability)
  • MSI can be detected in virtually all HNPCC, and
    15-20 of sporadic colon cancer.

8
  • What can we do to prevent it?

9
Screening
  • ASCO guideline start at age 50 with
  • Yearly FOBT or
  • Flex sig q5years or
  • Yearly FOBT Flex Sig q5yrs or
  • DCBE (Double contrast Barium enema) q5
  • Colonoscopy Q10yrs
  • CEA not good for screening, low PPV

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  • Why is colonoscopy every 10 years?

12
Pathophysiology
  • Unique model for multistep carcinogenesis
  • APC(5q21) -gt DCC(18q)-gtK-ras-gt P53
  • Prognostic value of
  • K-ras
  • LOH 18q
  • MSI (hMLH1, hMSH2)

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  • What are the Signs and symptoms of colon cancer?

16
Diagnosis (Signs and Symptoms)
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  • We suspect one, how do we work it up?

19
Diagnostic Evaluation
  • CT scan or Barium enema -gt colonoscopy and biopsy
  • CBC, Chem-7, LFT, CEA
  • CT scan of CAP

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Path Report Invasive Adenocarcinoma Grade
25
  • Okay now, we have a biopsy proven Colon Cancer,
    now what?

26
  • Everyone goes for surgery, unless widely
    metastatic!
  • ( Operability vs resectability )
  • Special cases
  • Liver metastasis Surgery or Neoadjuvant

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  • Okay the Surgeon took it all out.
  • Are we done?

31
AJCC Staging (TNM)
32
Adjuvant Chemotherapy
  • How effective is adjuvant chemotherapy and what
    is the benefit?

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  • The clear major benefit of adjuvant therapy is to
    significantly and meaningfully reduce this risk
    of early recurrence by approximately 40

35
  • Cure rate Vs mere delay in relpase (for Stage II,
    III)
  • ANSWER
  • January 26, 2009 in the Journal of Clinical
    Oncology
  • Metaanalysis-18 randomized clinical
    trials
  • gt28000 pts
  • 7 improvement in 8-year overall survival
    rate, compared with no treatment after surgery
  • ( stage II 5 , stage III 10 improvement.)
  • Noting that disease recurrence is unlikely or
    "minimal" after 8 years and does not exceed 0.5
    for both treated and untreated patients, "After 8
    years, the notion of cure is appropriate,"

36
  • So who gets adjuvant chemotherapy?
  • All stage III (IIIA, IIIB)
  • Some Stage II High Risk features
  • (as per MOSAIC trial lt12 LN, Obstruction,
    Perforation, LVI(), T4, High Grade)
  • (MSS, LOH18q E5202)

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  • So were convinced if Stage II or III colon
    cancer, I want chemotherapy.
  • What chemotherapy do I get?
  • For How long?

39
  • 5 Fluorouracil based regimens
  • 6months
  • Various regimens but we do have a standard
    regimen.
  • FOLFOX
  • FOLFIRI
  • IFL
  • 5FU LV (Roswell Park / Mayo clinic)

40
Evolution of Adjuvant Therapy
  • Intergroup 035 trial 5FULev NEJM1990
  • 41 decreased relapse rate
  • 33 decrease in cancer related mortality
  • National concensus give 5FU base adjuvant
    chemotherapy for all stage III colon cancers

41
  • Intergroup 0089 Proc Am Soc Clin Onc 1998
  • Randomized 3759 pts with stage II III to 4 arms
  • 5FU Lev for 12 months DFS 56 OS63
  • 5FU High dose LV DFS 60 OS 66
  • (Roswell Park Weekly regimen)
  • 5FU Low dose LV DFS 60 OS 66
  • (Mayo Clinic 5days q 4 weeks)
  • 5FU LV Lev DFS 60 OS 67

42
  • MOSAIC trial NEJM 2004
  • European study 2219 pts Stage II III
  • - Infusional 5FULV(IFL) 3yr DFS 72.9
  • - vs FOLFOX4 3yr DFS 78.2
  • Not much difference in OS
  • (recent bench mark of 17400 pts 3yr DFS
    5yr OS)
  • -gt thus, inferred benefit of OS

43
  • FOLFOX4 -gt FOLFOX6
  • omitted day2 of bolus 5FU LV
  • FOLFOX6 -gt mFOLFOX6
  • reduced dose of oxaliplatin from 100 to
    85mg/m2
  • (gt70 or maybe gt65 yo do not benefit from
    oxaliplatin)

44
Trade off for RFS and OS
  • Side effects!
  • Cytopenias
  • fatigue
  • Diarrhea (s-DPD, UGT1A1 mut)
  • Neuropathy ( cold neuropathy )
  • Skin darkening (5 FU)

45
  • Okay we went through 6months of adjuvant
    chemotherapy, now what?

46
Metastatic setting
  • How bad is it?
  • Why do patients see Oncologist?

47
Stage IV Chemotherapy!
48
Whats relatively New?
  • EGFR and K-Ras (BRAF) -Cetuximab
  • Panitumomab, Regorafenib(Stivarga)
  • VEGF and Bevacizumab(Avastin, Aflibercept)
  • Xeloda
  • COX-2
  • Stage II

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