clinical colorectal cancerclinical colorectal cancer · 2010. 4. 5. · 1. epidemiology -...
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Clinical Colorectal CancerClinical Colorectal Cancer
Abby Siegel MD, MS
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COLON CANCERCOLON CANCER1 Epidemiology1. Epidemiology2. Risk factors3. Manifestations4 Treatment4. Treatment
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1. EPIDEMIOLOGY
Colorectal cancer is the third- Colorectal cancer is the third most common cancer in the United States
- About 150,000 new cases/yearAbout 150,000 new cases/year- Most cases in people over 50
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Colorectal Cancer Incidence, 2008
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Colorectal Cancer Deaths, 2009
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EPIDEMIOLOGY
- Incidence rates high in U.S.,Europe AustraliaEurope, Australia
- Increasing in Japan- Low in China, Africa
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EPIDEMIOLOGY
- Changes in incidence rates over time and with ove t e a d w tmigration may indicate role
f i t l f tof environmental factors
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2 RISK FACTORS:2. RISK FACTORS: Protective
- Exercise- NSAIDS- ? Calcium/Vitamin D? Calcium/Vitamin D- ? Fiber
? F li A id- ? Folic Acid
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NSAIDS
1) Cox-1 and Cox-2 inhibition-Aspirin, Ibuprofenp , p-Bleeding risk
2) Selective Cox-2 inhibition)-Rofecoxib (Vioxx), -Celecoxib (Celebrex)( )-Thrombosis risk
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RISK FACTORSRISK FACTORS: Increased risk with…
-Advanced age
-Inflammatory bowel disease
-Consumption of high-fat diet
-Personal or family history of colon cancer
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FAMILIAL SYNDROMES
• HNPCC– Hereditary non-polyposis colon cancerHereditary non polyposis colon cancer
• APC• APC– Adenomatous polyposis coli
• Both usually autosomal dominant
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HNPCC (Lynch Syndrome)Hereditary Non-Polyposis Colon Cancer
• 2-5% of colon cancers• Caused by mutations in
mismatch repair genes• Tend to present in the right
colon• Often associated with
endometrial cancer in women
• Start screening early 20s
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HNPCC Increases the Risk of
By age 50By age 50 By age 70By age 70
Colorectal Cancery gy g y gy g
Population RiskPopulation Risk 0.2%0.2% 2%2%HNPCC RiskHNPCC Risk >25%>25% 80%80%HNPCC RiskHNPCC Risk >25%>25% 80%80%
Gastroenterology Gastroenterology 1996;110:10201996;110:1020--77Int J CancerInt J Cancer 1999;81:2141999;81:214--88
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HNPCC Increases the Risk of E d i l C
By age 50By age 50 By age 70By age 70
Endometrial Cancery gy g y gy g
Population RiskPopulation Risk 0.2%0.2% 1.5%1.5%HNPCC RiskHNPCC Risk 20%20% 60%60%HNPCC RiskHNPCC Risk 20%20% 60%60%
Gastroenterology Gastroenterology 1996;110:10201996;110:1020--77Int J CancerInt J Cancer 1999;81:2141999;81:214--88
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HNPCC: Cancer RisksHNPCC: Cancer Risks
100100
% with % with cancercancer
8080 ColorectalColorectal 78%78%
6060
4040 EndometrialEndometrial 43%43%4040
2020
Endometrial Endometrial 43%43%
Stomach Stomach 19%19%Biliary tract Biliary tract 18%18%U i t tU i t t 10%10%
002020 4040 6060 808000
Urinary tract Urinary tract 10%10%Ovarian Ovarian 9%9%
Aarnio M et al. Aarnio M et al. Int J CancerInt J Cancer 64:430, 199564:430, 1995
Age (years)Age (years)
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APCAPC Adenomatous Polyposis Coli
• Less than 1% of colon cancers• Caused by mutation of APC gene (5q21)• Also associated with duodenal cancers, ,
desmoid tumors, “CHRPE” (congenital hypertrophy of the retinal pigment epithelium)yp p y p g p )
• Start screening at puberty
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3. MANIFESTATIONS
1 Growth of cancer at primary site1. Growth of cancer at primary site
2. Metastatic spread
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MANIFESTATIONS
1. Growth of cancer at primary sitea Asymptomatic/screeninga. Asymptomatic/screeningb. Right sided syndromec. Left sided syndrome
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MANIFESTATIONS1. Growth of cancer at primary site
i Asymptomatici. Asymptomatic- Detected by screening test
- Fecal occult bloodFecal occult blood- Sigmoidoscopy- ColonoscopyColonoscopy- “Virtual” colonoscopy - Molecular techniquesq
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Virtual Colonoscopypy
Pickhardt et al. NEJM, 349 (23): 2191, 2003, ( ) ,
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Screening summary
• Average risk: colonoscopy every 10 years over age 50years over age 50
• Family history: colonoscopy 10 years b f i dbefore index case
• Dysplastic polyps: repeat colonoscopy y p p yp p pyafter 3 years
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Screening, continued…
• APC: annual flexible sigmoidoscopy starting at age 11, colectomy when polyps g g , y p ypdevelop
• HNPCC: colonoscopy at age 21 then everyHNPCC: colonoscopy at age 21, then every 1-2 years
• Inflammatory bowel disease: start 8 years• Inflammatory bowel disease: start 8 years after pancolitis, 12 years after distal disease
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MANIFESTATIONS1. Growth of cancer at primary site
ii. Right sided syndrome
a) Ascending colon has thin wall, large diameter, distensibleg ,b) Liquid fecal streamc) Chronic blood loss results in iron d fi i i ***deficiency anemia***d) Obstruction unlikely
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MANIFESTATIONS1. Growth of cancer at primary site
iii. Left sided syndromea) Descending colon wall thicker, less
distensibleb) More solid fecal streamb) More solid fecal streamc) Tumors tend to infiltrated) Bright red blood more common) ge) Obstruction more common
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“Apple core lesion”
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COMPARISON RIGHT AND LEFT SIDED COLON CANCERS
Ri ht L ftRight LeftAnemia +++ +Occult bleeding +++ +Gross bleeding + +++Abd. Mass ++ +Change in bowel + +++g
habitsObstruction + +++Obstruction
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Stage Stage 11 Colorectal CancerColorectal Cancer•• 23% of colorectal CA23% of colorectal CA•• Cancer has grown Cancer has grown
h h hh h hthrough the mucosa through the mucosa and invades the and invades the muscularismuscularismuscularismuscularis
•• Treatment: surgery to Treatment: surgery to remove the tumor and remove the tumor and some surrounding some surrounding lymph nodeslymph nodes
•• Survival: 93%Survival: 93%
Adapted from www.plwc.org, 2007
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Stage Stage 22 Colorectal CancerColorectal Cancer31% f l l CA31% f l l CA•• 31% of colorectal CA31% of colorectal CA
•• Cancer grows Cancer grows beyond the beyond the muscularismuscularis of the colon orof the colon ormuscularis muscularis of the colon or of the colon or rectum but has not spread rectum but has not spread to the lymph nodesto the lymph nodes
•• Treatment (colon): surgery Treatment (colon): surgery +/+/-- adjuvant chemotherapyadjuvant chemotherapyS i l 2 8 %S i l 2 8 %•• Survival: 72 to 85%Survival: 72 to 85%
•• Treatment (rectal): surgery, Treatment (rectal): surgery, radiation and chemoradiation and chemoradiation and chemoradiation and chemo
Adapted from www.plwc.org, 2007
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Stage Stage 33 Colorectal CancerColorectal Cancer•• 26% of colorectal CA26% of colorectal CA•• Cancer has spread to the Cancer has spread to the
i l l h di l l h dregional lymph nodesregional lymph nodes•• Treatment (colon): surgery Treatment (colon): surgery
and adjuvantand adjuvantand adjuvant and adjuvant chemotherapychemotherapy
•• Survival: 44 to 83%Survival: 44 to 83%•• Treatment (rectal): surgery, Treatment (rectal): surgery,
radiation and radiation and h thh thchemotherapychemotherapy
Adapted from www.plwc.org, 2007
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Stage Stage 4 4 Colorectal CancerColorectal Cancer•• 20% of colorectal CA20% of colorectal CA•• Cancer has spread to Cancer has spread to
other areas of the bodyother areas of the body•• Treatment: chemotherapy. Treatment: chemotherapy.
Consider surgery of Consider surgery of primary lesion especiallyprimary lesion especiallyprimary lesion, especially primary lesion, especially if symptomaticif symptomatic
•• Surgery to removeSurgery to removeSurgery to remove Surgery to remove metastases (liver/lung) in metastases (liver/lung) in carefully selected patientscarefully selected patients
•• Survival: 8%Survival: 8%Source: UpToDate.com, 2007
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PROGNOSIS depends on…
1. Histological features- poor differentiation- poor differentiation-vascular invasion
2 Depth of invasion2. Depth of invasion3. Nodal involvement4 Genetic alterations4. Genetic alterations
-18q LOH (bad), MSI (good), K-ras mutation (limits response to anti-EGFR antibodies)(limits response to anti-EGFR antibodies)
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MANIFESTATIONS
Metastatic Spread1 L h ti1. Lymphatics
Mesenteric nodesVirchow’s node
2. Hematogenous spreadg pLiver via portal circulation
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LIVER METASTASES
MANIFESTATIONS1. Pain (stretching capsule)2. Hepatomegaly, nodularityp g y y3. Elevated liver function tests
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4 TREATMENTS4. TREATMENTS1 Surgery1. Surgery
-Localized disease (Stage I, II, III)-Try to remove isolatedTry to remove isolated metastases
2. Radiation therapy py-Rectal cancer-helps prevent local recurrence
3. Pharmaceuticals-Stage III and IV disease
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TREATMENT: Pharmaceuticals
1. 5-Fluorouracil1. 5 Fluorouracil - pyrimidine antimetabolite
2 Irinotecan2. Irinotecan- topoisomerase inhibitorprevents re ligation after cleavageprevents re-ligation after cleavage of DNA by topoisomerase I
3 Oxaliplatin3. Oxaliplatin- alkylating agent, causes formation of bulky DNA adductsformation of bulky DNA adducts
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Exciting new biologics…
4. Bevacizumab -Antibody against VEGF-May block angiogenesis and also stabilize leaky vasculature
5 Cetuximab Panitumomab5. Cetuximab, Panitumomab-Antibodies against EGFR-Binds to EGF receptor on tumor pcells, prevents dimerization and cell signaling
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Bevacizumab toxicities
• Bleeding• ThrombosisThrombosis• Hypertension
W d h li li i• Wound healing complications• Half life about 3 weeks; wait at least 2 half-
lives before major surgery
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EGFR inhibition and rash
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Correlating Survival With SkinCorrelating Survival With Skin Rash
14P = .0008* P = .0007*
10
12
14
P = .04*
G2G1G0
urvi
val
6
8
10
P = .0002*
G3G2Su
2
4
9923/CRC 9814/Pancreas9816/SCCHN0
0141/CRC
* Log-rank P value, grade 0 vs. grades 1-3
Saltz L et al. Proc Am Soc Clin Oncol 2003; 22:204 (abstract 817)Slide courtesy of Josep Tabernero, MD
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Original Article
Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer
Eric Van Cutsem, M.D., Ph.D., Claus-Henning Köhne, M.D., Erika Hitre, M.D., Ph.D., Jerzy Zaluski, M.D., Chung-Rong Chang Chien, M.D., Anatoly Makhson, M.D., Ph.D.,
Geert D'Haens, M.D., Ph.D., Tamás Pintér, M.D., Robert Lim, M.B., Ch.B., György Bodoky, M.D., Ph.D., Jae Kyung Roh, M.D., Ph.D., Gunnar Folprecht, M.D., Paul Ruff,Bodoky, M.D., Ph.D., Jae Kyung Roh, M.D., Ph.D., Gunnar Folprecht, M.D., Paul Ruff, M.D., Christopher Stroh, Ph.D., Sabine Tejpar, M.D., Ph.D., Michael Schlichting, Dipl.-
Stat., Johannes Nippgen, M.D., and Philippe Rougier, M.D., Ph.D.
N Engl J MedVolume 360(14):1408-1417
April 2, 2009
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BevacizumabVEGF
Cetuximab, Panitumomab
Molecularly Targeted Therapy in Oncology
VEGFRPDGFR EGFR
P P P P
P13K
STAT
PP P P P PP PSunitinibSorafenib
SunitinibSorafenib
Raf
RasAKT
STAT
mTORSorafenib
GefitinibErlotinib
Mek
HIF-1α HIF-1β
Transcription Factors
CCI-779RAD001
Nucleus
Survival/↓
Cell proliferationAngiogenesis Metastases↓Apoptosis
Slide courtesy of Wells Messersmith, MD
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Hazard Ratios for Progression-free and Overall Survival and Odds Ratios with Tumor Response, According to the Mutation Status of KRAS in the Tumor
Van Cutsem E et al. N Engl J Med 2009;360:1408-1417
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BevacizumabVEGF
Cetuximab, Panitumomab
Molecularly Targeted Therapy in Oncology
VEGFRPDGFR EGFR
P P P P
P13K
STAT
PP P P P PP PSunitinibSorafenib
SunitinibSorafenib
Raf
RasAKT
STAT
mTORSorafenib
GefitinibErlotinib
Mek
HIF-1α HIF-1β
Transcription Factors
CCI-779RAD001
Nucleus
Survival/↓
Cell proliferationAngiogenesis Metastases↓Apoptosis
Slide courtesy of Wells Messersmith, MD
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TREATMENTPh ti lPharmaceuticals
1. “Adjuvant” (after surgery) C i l i i fCurative goal in patients after complete resection
2 P lli ti i ti t ith2. Palliation in patients with gross metastatic disease
3 “Neoadjuvant” (before surgery)3. Neoadjuvant (before surgery) Shrink tumors, then try to resect in limited metastatic diseaselimited metastatic disease
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TREATMENT:TREATMENT:Metastatic disease
• Systemic chemotherapy now has improved survival for those with metastatic disease to about 2 years
• We now sometimes treat neoadjuvantly (before surgery), shrinking metastases and then surgically removing them
• This is important, because some of these “limited metastases” patients are cured!
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Trends in the Median Survival of Patients with Advanced Colorectal Cancer
Meyerhardt, J. A. et al. N Engl J Med 2005;352:476-487
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Estimated drug costs for eight weeks of treatmentEstimated drug costs for eight weeks of treatment for metastatic colorectal cancer
25000
30000
15000
20000
25000
5000
10000
15000 Cost in $
0
5000
5FU Combo Antibody
Schrag, D. N Engl J Med 2004;351:317-319
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Conclusions:• Know HNPCC and APC—these may help you
prevent cancers in others• Understand how colon cancer commonly presents• Understand how colon cancer commonly presents
(right versus left-sided), and common sites of spread
hi k b l ( h ) i ld• Think about colon (or other GI) cancer in an older person with iron-deficiency anemia—don’t just give them iron!g
• Don’t give up on those with metastatic disease with new treatment options and occasionally cures
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• My email:My email:
54@ l bi d• [email protected]
• Many thanks to Tom Garrett for several slides!seve s des!