Colon Cancer Overview

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Colon Cancer

• Sung Ho Lee, MD
• Hematology and Medical Oncology

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• How common and serious is Colon Cancer ?

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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

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

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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

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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)

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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.

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• What can we do to prevent it?

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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?

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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?

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

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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
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• Okay now, we have a biopsy proven Colon Cancer,
  now what?

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• 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?

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AJCC Staging (TNM)
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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

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• 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,"

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• 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?

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

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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

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• 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

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• 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

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• 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)

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Trade off for RFS and OS

• Side effects!
• Cytopenias
• fatigue
• Diarrhea (s-DPD, UGT1A1 mut)
• Neuropathy ( cold neuropathy )
• Skin darkening (5 FU)

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

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Metastatic setting

• How bad is it?
• Why do patients see Oncologist?

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Stage IV Chemotherapy!
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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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