Adjuvant Chemotherapy in Colorectal Cancer

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Adjuvant Chemotherapy in Colorectal Cancer

• Research project presentation
• Jun Sun
• July 24, 2006

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Colorectal Caner

• 150,000 new cases with 50,000 death a year in the
  United States(2nd leading cause of death)
• Risk factors include FAP, HNPCC, IBD (10-15)
  history of CRC, or adenomas, first-degree family
  history of colorectal cancer or adenomas and a
  personal history of ovarian, endometrial, or
  breast cancer (23) age, smoking, heavy EtOH,
  high fat/low fiber Diet.

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Adjuvant Chemotherapy
PATHOLOGIC STAGE
ADJUVANT THERAPY
SURVEILLANCE
Tis T1, N0, M0 T2, N0, M0
None
Consider capecitabine or 5-FU/LV or
5-FU/leucovorin/oxaliplatin (category 2B for all
options) or Clinical trial or Observationi
T3, N0, M0 (no high risk features)

• History and physical every 3 mo for 2 y,
• then every 6 mo for a total of 5 y
• CEA every 3 mo for 2 y, then every 6
• mo for a total of 5 y for T2 or greater
• lesions
• Colonoscopy in 1 y, repeat in 1 y if
• abnormal or at least every 2-3 y if
• negative for polyps. If no preoperative
• colonoscopy due to obstructing lesion,
• colonoscopy in 3-6 mo.
• PET scan is not routinely
• recommended
• Chest/abdominal/pelvic CT may be
• considered annually x 3 y for patients
• at high risk for recurrence,

T3, N0, M0 high risk for systemic
recurrence Grade 3-4, lymphatic/ vascular
invasion, bowel obstruction, examined or T4, N0, M0 or T3 with localized
perforation or close, indeterminate or positive
margins
5-FU/leucovorin/oxaliplatin or capecitabine or Cl
inical trial or Observation or 5-FU/leucovorin
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Adjuvant Chemotherapy
PATHOLOGIC STAGE
ADJUVANT THERAPY
SURVEILLANCE

• History and physical every 3 mo for 2 y,
• then every 6 mo for a total of 5 y
• CEA every 3 mo for 2 y, then every 6
• mo for a total of 5 y for T2 or greater
• lesions
• Colonoscopy in 1 y, repeat in 1 y if
• abnormal or at least every 2-3 y if
• negative for polyps. If no preoperative
• colonoscopy due to obstructing lesion,
• colonoscopy in 3-6 mo.
• PET scan is not routinely
• recommended
• Chest/abdominal/pelvic CT may be
• considered annually x 3 y for patients
• at high risk for recurrencem,

5-FU/leucovorin/oxaliplatin (category1) or 5-FU/le
ucovorin or Capecitabine
T1-3, N1-2, M0 or T4, N1-2, M0
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CHEMOTHERAPY FOR ADVANCED OR METASTATIC DISEASE
First-line therapy
Second-line therapy
Third-line therapy
Fouth-line therapy
FOLFIRI or Irinotecan
Irinotecan cetuximab
FOLFOX Bevacizumab
Irinotecan cetuximab
FOLFIRI bevacizumab
FOLFOX or Irinotecan cetuximab
FOLFOX

• Patient can tolerate intensive therapy

IFL4 bevacizumab
Irinotecan cetuximab
FOLFOX or Irinotecan or FOLFIRI
Irinotecan
5-FU/leucovorin bevacizumab
Irinotecan cetuximab
Irinotecan or FOLFIRI
CAPOX bevacizumab
Irinotecan cetuximab
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CHEMOTHERAPY FOR ADVANCED OR METASTATIC
DISEASE(cont.)
First-line therapy
Capecitabine Or Bolus 5-FU leucovorin
bevacizumab (category 2B) Or Infusional 5-FU
leucovorin bevacizumab (category
2B) Or Protracted 5-FU leucovorin
Improvement in functional status No improvement
in functional status
Consider second-line Therapy Best supportive care

• Patient can Not tolerate intensive therapy

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Fluorouracil (5-FU)

• A fluorinated pyrimidine that inhibits
  thymidylate synthase in pyrimidine nucleotide
  synthesis.
• Usually administered with leucovorin, a reduced
  folate (folinic acid), that enhancing inhibition
  of DNA synthesis by stabilizing binding of
  fluorouracil to thymidylate synthase.
• Major side effects depend on the method of
  administration
• Neutropenia and stomatitis with daily bolus
  treatments
• Diarrhea with weekly bolus doses
• Hand-foot syndrome, and some GI toxicity with IV
  continuous infusion

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Capecitabine(Xeloda)

• Capecitabine, a fluoropyrimidine carbonate, is
  the only oral fluoropyrimidine commercially
  available in the United States for the treatment
  of advanced colorectal cancer.
• Capecitabine was a custom designed 5-FU
  pro-drug that was developed to improve
  tolerability of 5-FU.
• Capecitabine is absorbed intact through the
  gastrointestinal mucosa and is metabolized in the
  liver to 5-deoxy-5-fluorocytosine and to
  doxifluridine. Doxifluridine is then converted by
  the enzyme thymidine phosphorylase, which is
  found in high concentrations in tumor tissue, to
  5-FU.
• The side-effect profile is similar to that
  observed when 5-FU is given as protracted
  infusion.

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Capecitabine vs. 5-fluorouracil
Capecitabine (Xeloda)
5-Fluorouracil (5-FU)
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Metabolic Pathway of capecitabine to 5-FU
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Mechanism of Action of capecitabine and 5-FU
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Maintenance chemotherapy with capecitabine

• Retrospective study of patients that have been on
  maintenance capecitabine for various GI related
  malignancies
• To review the toxicity/safety profile of such a
  regiment to ensure tolerability and feasibility
  of such therapy

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References

• YM. Rustum. Thymidylate Synthase A critical
  target in Cancer Therapy? Frontiers in Bioscience
  9, 2467-2473, September 1, 2004.
• CM. Walko, C. Lindley. Capecitabine A review.
  Clinical Therapeutics, Volume 27, issue 1,
  January 2005, Pages 23-44
• National Comprehensive Caner Network Practice
  Guidelines. www.hccn.org
• The Internet Drug Index www.rxlist.com
• JA Meyerhardt, RJ Mayer. Systemic therapy for
  colorectal Cancer. New England Journal of
  Medicine 2005352276-87.

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Questions?