Colorectal Cancer • The third most common cancer in U.S.
Colorectal Cancer Overview Issam Makhoul, M.D. University of Arkansas for Medical Sciences April 24, 2009
• 148,810 new cases in 2008 • The second deadliest cancer • 49,960 deaths nationwide • > 1 million Americans living with h/o CRC
CRC Risk Factors
Anatomy
NonNon-Modifiable Risks • Age Hepatic flexure
– 90% of cases occur in people 50 and older Transverse
Splenic flexure
Ascending Descending
Sigmoid Rectum
• Gender – slight male predominance, but common in both men and women
• Race/Ethnicity – African Americans have highest incidence and mortality rate of all groups in U.S., Hispanics the lowest – Increased rates also documented in Ashkenazi Jews
CRC Risk Factors
CRC Risk Factors
NonNon-Modifiable Risks:
Modifiable Behavioral Risk Factors
• Personal history of inflammatory bowel
• Tobacco
disease, adenomatous polyps or colon cancer • Family history of adenomatous polyps,
colon cancer, other conditions ( i.e. inherited mutations such as FAP, HNPCC)
*Individuals with these risk factors are at high risk and may require earlier and more intensive screening
• Alcohol • Physical inactivity • Obesity • Diet (high fat –especially red & processed meats; low fruit and vegetables)
Red Meat and Colon Cancer
Relative Risk of Developing Colon Cancer
1.5 1.4
1.45
1.3
1.31
1.29
1.2 1.16
1.1 1 1
0.9 0.8 29
Relative Risk of Developing Colon Cancer
Obesity and Colon Cancer
2 Giovannucci Cancer Res 1994
1.8 1.71
1.6 1.4 1.2 1.21
1 1 1
2
3
4
5
Inherited Risk of CRC Sporadic (average risk) (65%– (65%–85%)
1
Relative Risk of Colon Cancer
0.98
Quintile of Red Meat Intake
Martinez JNCI 1997
Physical Activity & Colon Cancer
0.97
0.8
1 0.8 0.78 0.71
0.6
0.67 Family history (10%– (10%–30%)
0.54
0.4
Rare syndromes (90%
5-year survival
B2 C1 C2 D Through Not through Through Distant bowel wall bowel wall: bowel wall: metastases lymph node lymph node metastases metastases 70–75% 50–65% 25–45% 50 years Results: Results:
•
If the full range of screening tests are not available, physicians should make every effort to offer at least one test from either category
32% (95% CI,29.8%CI,29.8%-35.3%) inin-office based single sample FOBT 41.2%(38.8%41.2%(38.8%-44%) used both inin-office single sample and home FOBT 29.7% ( CI,27%CI,27%-32.4%) recommended repeating FOBT instead of offering colonoscopy for positive FOBT
Sensitivity of FOBT Take Home & InIn-Office
2008 CRC Screening Guidelines: Two new tests recommended
Sensitivity FOBT method (Hemoccult II)
All Advanced Lesions
Cancer
23.9 %
43.9 %
4.9 %
9.5 %
• Stool DNA (sDNA)
3 card, taketake-home Single sample, ininoffice
• Computed tomographic colonography (CTC) –”virtual colonoscopy” colonoscopy”
• Take home message: In-office FOBT is essentially worthless as a screening tool for CRC and is strongly discouraged Collins et al, Annals of Int Med Jan 2005
Genetic Model of CRC
Stool DNA Test (sDNA) Rationale • Colon cells are shed Mutation
continuously • Polyps and cancer cells contain abnormal DNA • Stool DNA tests detect abnormal DNA from cells that are passed in the stool* ( compared to FOBT which detect intermittent blood) blood)
Bat-26 (Sporadic)
Bat-26 (HNPCC) APC
Normal Epithelium
p53
K-ras
Adenoma
Dwell Time: Many decades
Late Adenoma
2-5 years
2-5 years
Optimum phase for early detection
*All positive tests should be followed with colonoscopy
sDNA - Sample Collection
Courtesy of Barry M. Berger. MD, FCAP EXACT Sciences
sDNA: Evidence Three versions of the Exact Sciences test
Study with OneOneTime Testing (v) Ahlquist, et al
Collection bucket inserted into bracket and installed under toilet seat
Patient supplies whole stool sample; no diet or medication restrictions
Patient seals sample in outer container and freezer pack
Late Cancer
Early Cancer
Patient seals container and ships back to designated lab (all packing materials and labels supplied)
Version 1 (K(K-ras, APC, p53,BATp53,BAT-26, DIA) was evaluated in the Imperiale trial Version 1.1 (K(K-ras, APC, P53), PreGenPreGen-Plus is the currently marketed test Version 2 (Vimentin only, or Vimentin + DIA) is currently under evaluation Earlier and more recent versions were evaluated in smaller, mixed populations
Sensitivity for Cancer 91%
Gastro, 2000 (1)
Imperiale, et al
51.6%
NEJM, 2004 (1)
Syngal, et. al
63%
Cancer, 2006 (1)
Whitney, et al
70%
J Mol Diagn, 2004 (1.1)
Chen, et al
46%
JNCI, 2005 (2)
Itzkowitz, et al DDWDDW- AB, 2006 (2)
88%
sDNA: sDNA: Potential Advantages
sDNA: sDNA: Limitations • Misses some cancers
• No dietary restrictions needed • Sensitivity for adenomas with current test is low
• Specificity for cancer may be
significantly higher than other forms of stool testing • No stool sampling required
• Technology and test versions are in transition • Appropriate rere-screening interval is not known • Costs (approximately $300 - $400 per test) • Not covered by most insurers
(entire bowel movement collected) • Uncertainty about subsequent follow up of positive stool
• CompanyCompany-sponsored studies report high
levels of patient acceptance
CT Colonography (CTC)
DNA test if colonoscopy is negative • FDA approval concerns
CT Colonography 2-D view
CTC Image
Optical Colonoscopy
3-D view
Polyp
Courtesy of Beth McFarland, MD
Courtesy of Beth McFarland, MD
CTC vs. Optical Colonoscopy: Sensitivities for All Polyps Polyp Size
CTC Colonoscopy
>10mm
>8mm >6mm
93.8%
93.4% 88.7%
88.2%
89.5% 90.0%
CTC: Additional Findings CTC identified 55 polyps not seen on initial colonoscopy – 21 adenomas – One 11 mm malignant polyp ExtraExtra-colonic findings – 5 asymptomatic cancers (outside of the colon) – Aortic aneurysms – Renal and gall bladder calculi
Pickhardt et al, NEJM 2003
Pickhardt et al, NEJM 2003
CT Colonography: Advantage • Detailed evaluation of the entire colon
CT Colonography: Limitations • Requires full bowel prep • Colonoscopy is required if abnormalities
• Minimally invasive
detected ( second bowel prep)
(rectal tube for air insufflation) • ExtraExtra-colonic findings can lead to additional
• No sedation required
testing • Controversy re management of small polyps • Radiation exposure
Four Essentials for Improved Screening Rates
CT Colonography : Quality Issues • Steep learning curve for radiologists
Health Professional’ ’s Professional’s Professional Recommendation
• Limited availability to high quality
An Office Policy
exams in many parts of the country • Most insurers do not currently cover it
An Office Reminder System An Effective Communication System
Adjuvant Therapy of Colon Cancer
Adjuvant Treatment of Colon Cancer
Capecitabine ~ 5-FU/LV
5-FU/Lev 5-FU/LV > 55-FU/Lev
5-FU/LV
LV5FU2 ~ monthly bolus
6 ~ 1212-month treatment Lev unnecessary High ~ lowlow-dose LV
FOLFOX4 > 5-FU/LV
Monthly ~ weekly Rx
1990
1994
1998
2000
2002 2004
Adjuvant Therapy in Stage II Colon Cancer
Adjuvant Therapy for CRC What do we do with Stage II patients? What is the standard of care for stage III CRC? Is capecitabine an option in the adjuvant setting? What about patients >70 years old? Will biologics play a role in adjuvant Rx?
QUASAR: Overall Survival 100
The benefit would not exceed 5%
MetaMeta-analysis of Stage II Adjuvant Therapy
Observation (n=1622)
Adjuvant therapy does not appear to have any significant clinical benefits on stage II cancer
Chemotherapy (n=1617)
80
% of patients
IMPACT Meta-analysis Meta Meta-analysis NSABP analysis, Mamounas Seer Analysis, Schrag Gill Model QUASAR trial ASCO guidelines
60 40 P=0.02 5-year OS: Observation 77.4% vs Chemotherapy 80.3% Relative risk 0.83 (95% CI, 0.71-0.97)
20 0
0
1
2
3
4
5
6
7
8
9
10
Years Gray et al. ASCO, 2004. Abstract 3501. At: http://www.asco.org/ac/1,1003,_12-002511-00_18-0026-00_19-0010698,00.asp. Accessed November 2004.
Copyright © American Society of Clinical Oncology Benson,
MOSAIC Overall Survival: Stage II and Stage III
DiseaseDisease-free Survival: HighHigh-risk Stage II Patients
1.0
1.0
p=0.996
0.9
0.9
0.8
p=0.029
0.1%
0.8
0.7
0.7
4.4%
0.6 0.5 0.4 0.3
HR [95% CI]
0.2
Stage II
1.00 [0.71–1.42]
0.1
Stage III
0.80 [0.66–0.98]
FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III
Probability
Probability
A. B. et al. J Clin Oncol; 22:3408-3419 2004
7.2%
FOLFOX4 n=286
0.6
LV5FU2
n=290
0.5 0.4
3-year
5-year
0.3
FOLFOX4
85.4%
82.1%
0.2
LV5FU2
80.4%
74.9%
HR [95% CI]: 0.74 [0.52–1.06]
0.1
High-risk stage II- defined as at least one of the following: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion ,