Gastrointestinal Tract Cancer Prevention - CCCUPR 4-13-13.pdf · NCI/DCP/GOCRG • Umar • 2013...

NCI/DCP/GOCRG • Umar • 2013

Gastrointestinal Tract Cancer Prevention

Asad Umar, DVM, PhD Gastrointestinal & Other Cancers Research Group

Division of Cancer Prevention National Cancer Institute, NIH, USA


BAX

p53

-catenin/

E-cadherin

Chromatin

Remodeling/

Methylation

MSH2/

MLH1

TGF-RII

K-ras

SMAD2/4

AKT

ODC

APC

MMPs

TXNIP

Telomerase

Chronic Disease

Multiple Targets for Intervention

Gastrointestinal Tract:

Colorectal Cancer


Can

cer

Pro

gre

ssio

n

Time (Years)

Precancer

Carcinoma in situ

Metastasis

Cancer

Normal

Cancer Mortality

Survival without Cancer

Survival with Cancer Ad

apte

d f

rom

Um

ar

et a

l., 2

01

2. F

utu

re D

irec

tio

ns

in C

an

cer

Pre

ven

tio

n.

Na

ture

Rev

iew

s C

an

cer.

20

12

Impact of Cancer Preventive Interventions on Carcinogenic Progression


Worldwidea

(2008)

USAb

(2013)

Incidence

Mortality

1,234,000

608,000

142,820

50,830 8.9 % of all cancer

deaths (WHO, 2002) 3nd leading cause of cancer death

Colorectal Cancer: Scope of the Problem

a. GLOBOCAN 2008 (IARC) , Section of Cancer Information (10/4/2013

b. Siegel et al., 2013 CA Cancer J Clin 63: 11-30.

http://www-dep.iarc.fr/









CRC Trends in Puerto Rico • Annual increases in PR CRC incidence & mortality

(1987-2004)

• In contrast, in US CRC incidence and mortality rates

decreased for NHW, NHB, and USH during the

same time period

• A health disparity that warrants further investigation as well as

better approaches for early detection and cancer prevention in PR

Soto-Salgado et al., Cancer 2009


Risk Factors – Age > 50 – Unhealthy diet

• Excess caloric intake • Low fruits & vegetables • High-fat, low-fiber diet

– Unhealthy lifestyle • Tobacco use • Low physical activity

– Infectious Agents? • Fusobacterium nucleatum • HPV?

– Hereditary syndromes • FAP • HNPCC

– Chronic inflammatory bowel disease

– Personal history of colorectal neoplasia

– Family history of colorectal neoplasia

– First degree relatives - 2-3x risk

Implications

– Risks are individualized, Must be assessed and discussed

– Healthcare provider

– Family members

Major Risk Factors for Colorectal Cancer


Alarming Colorectal Cancer Incidence Trends: A Case for Early Detection and Prevention

Umar & Greenwald. Cancer Epi. Biom. Prev. 2009


tumor-promoting

inflammation

Avoiding immune

destruction

deregulating cellular

energetics

genomic instability

& mutations

enabling characteristics

emerging hallmarks

Adapted from Hanahan & Weinberg. Cell.2011:144.


• Analgesic

• Antipyretic

• Anti-inflammatory

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

The term "non-steroidal" distinguishes these drugs from steroids, which, among a broad range of other effects, have a similar eicosanoid-decreasing, anti-inflammatory action


Common Pharmacological Effects

• Analgesic (CNS and peripheral effect) may involve non-PG related effects

• Antipyretic (CNS effect)

• Anti-inflammatory due mainly to Prostaglandin inhibition


Pharmacological Effects (cont’d)

• Diverse group of chemicals, but all inhibit cyclooxygenase

• Inhibition of PG synthesis is largely responsible for their therapeutic effects

• But, inhibition of PG synthase in gastric mucosa dyspepsia, gastritis


Cyclo-oxygenase (COX)

• Constitutively expressed isoform (COX-1)

• At site of inflammation, cytokines stimulate the induction of the 2nd isoform (COX-2)

• Inhibition of COX-1 is responsible for their GI toxicity

• Most currently used NSAIDs are somewhat selective for COX-1, but selective COX-2 inhibitors are available


Qu

alit

y o

f Ev

ide

nce

In Vitro (Test Tube), Preclinical Studies

Observational (Case-Control) Studies

Observational (Cohort) Studies

Randomized Trials

Systematic Reviews

Cancer Preventive Efficacy: Hierarchy of Quality of Evidence


Inflammation Carcinogenesis

Cancer Inflammatory Stimulus or Condition

Bladder Cancer Schistosomiasis, Cystitis

Cervical Cancer Human Papilloma Virus, Cervicitis

Colorectal Cancer Inflammatory Bowel Disease, Colitis

Esophageal Adenocarcinoma Esophagitis, Barrett’s metaplasia

Gall Bladder Cancer Cholecystitis

Gastric Cancer H. pylori induced gastritis

Hepatocellular Cancer Hepatitis Viruses (B and C)

Lung Cancer Bronchitis

Pancreatic Cancer Pancreatitis

Prostate Cancer Prostatitis


Normal Colorectal Cancer

Inflammation in Colorectal Cancer

Red color indicates upregulation of the COX-2 enzyme.

The COX-2 enzyme is upregulated in human colorectal cancer


Normal Lung Cancer Red color indicates upregulation of the COX-2 enzyme.

The COX-2 enzyme is upregulated in human lung cancer

Inflammation in Lung Cancer


Normal Prostate Cancer Red color indicates upregulation of the COX-2 enzyme.

The COX-2 enzyme is upregulated in human prostate cancer

Inflammation in Prostate Cancer


NSAIDs in Preclinical Models

NSAID In Vitro ACF Colon Mammary Lung Bladder Esophagus Head/Neck Prostate Skin

Aspirin +++ ++ +++ - Ongoing ++

Celecoxib +++ ++ +++ ++ - +++ - + - +++

Naproxen + +++ Ongoing + +++

Sulindac +++ ++ +++ - - +++ Ongoing +++ ++

- No Benefit

+ ≥ 25% Benefit

++ ≥ 50% Benefit

+++ ≥ 75% Benefit


• Retrospective • Prospective

0.58

0.6

0.51

0.68

Thun ‘91 - Women

Thun ‘91 - Men

Giovannucci ’94

Bansal ‘96

NSAIDs Use and Colon Cancer-Associated Mortality

Estimated Relative Risk

0 1 2

Observational Studies:



0.6

0.74

Estimated Relative Risk 0 1 2

0.5

0.24

0.08

0.54

0.7

0.68

0.56

1.5

1.07

0.25

0.32

0.64

0.76

Kune ‘88

Rosenberg ‘91

Suh ’93 -Men

Suh ’93 -Women

Peleg ‘94

Schreinemachers ‘94

Giavannuci ‘94

Paganini-Hill ‘95

LaVeccia ‘97

Strumer ‘98

Peleg ’96

Muscat ’94-Women

Muscat ’94-Men

Langham ‘00

Giavannuci ‘95

NSAIDs Use and Colorectal Cancer Incidence Observational Studies:



0.52

Estimated Relative Risk 0 1 2

0.6

0.49

0.56

0.65

0.6

0.31

0.21

Aspirin

Greenberg ‘93

Suh ’93

Rodriguez ‘00

NSAIDs

Giavannuci ‘94

Martinez ‘95

Peleg ‘96

Sandler ’98

Breuer-Katchinski ‘00

Logan ‘93

NSAIDs Use and Colorectal Adenoma Incidence Observational Studies:

0.36


Growth, Anti-Apoptosis, Migration, Invasion, Angiogenesis

(5-Lipoxygenase)

Leukotriens [Inflammation/Asthma]

Inflammation (NF-kB) Signaling

(Cyclooxygenase 1/2) Prostaglandins

[Inflammation]

Cell Membrane

Programmed Cell Death (Apoptosis)

Signaling

Nucleus

PPARa/g PPARd NF-kB EGFR

Arachidonic Acid

Prostaglandins

How Aspirin/NSAIDs Protect Against Cancer?

Inflammatory Signal


Growth, Anti-Apoptosis, Migration, Invasion, Angiogenesis

(5-Lipoxygenase)

Leukotriens [Inflammation/Asthma]

Inflammation (NF-kB) Signaling

(Cyclooxygenase 1/2) Prostaglandins

[Inflammation]

Cell Membrane

Programmed Cell Death (Apoptosis)

Signaling

Nucleus

PPARa/g PPARd

Non-Steroidal Anti-Inflammatory Drugs

(Aspirin/NSAIDs)

NF-kB EGFR

Arachidonic Acid

Prostaglandins

Inflammatory Signal

How Aspirin/NSAIDs Protect Against Cancer?


Immune Function

Carcinogenesis

Prostaglandins (PGE2)

Arachidonic

Acid

Free Radical Production Carcinogen Activation

Proliferation

Angiogenesis

Apoptosis

COX-2

COX

inhibitor X COX-1

Sphingomyelin Ceramide

Non-COX Targets: P450s PPAR/g PPARa,g

X


0.58

0.83

0.64

0.73

Baron’03- 81 mg/d

Baron’03- 325 mg/d

Sandler’03 – 325 mg/d [12.8 mo]

Benamouzig’03 – 300 mg/d [12 mo]

Aspirin and Colorectal Adenoma Prevention

Relative Risk

0 1 2

Randomized Clinical Trials:

P=0.022

P=0.13

P=0.13

P=0.08


Colorectal Adenoma Prevention Studies:

Relative Risk of Adenoma Recurrence


Percent Change in Number of Percent Change in Number of Colorectal Polyps with Celecoxib Colorectal Polyps with Celecoxib

(Individual Patients; Median Results)(Individual Patients; Median Results)

Pe

rcen

t C

ha

ng

e f

rom

Ba

se

lin

eP

erc

en

t C

ha

ng

e f

rom

Ba

se

lin

ePlaceboPlacebo

N=15N=15100 mg BID100 mg BID

N=32N=32400 mg BID*400 mg BID*

N=30N=30

--8080

--6060

--4040

--2020

00

2020

4040

6060

8080

0%0% --7%7%

--32%32%

* P = 0.003 versus placebo* P = 0.003 versus placebo Steinbach, et al. NEJM, 2000

Randomized Trials of Celecoxib in Patients with FAP & Sporadic CRC


Patient 5120

400 mg BID

Patient 5120

400 mg BID

Baseline polyp number = 41Baseline polyp number = 41 6 Month polyp number = 216 Month polyp number = 21

Percent change = Percent change = -- 48.8%48.8%2


age > 30 or older with colorectal adenomas:

6 mm diameter or multiple adenomas

Randomized to:

celecoxib 200mg bid * celecoxib 400mg bid * placebo bid

N=671 N=685 N=679 *stratified by low-dose aspirin use and clinical center

Primary Endpoint: adenoma detected

at any post-randomization

colonoscopy

Bertagnolli, et al., 2006

Adenoma Prevention with Celecoxib (APC)

Colon polyps

Colonoscopy Year 1, 3 and 5

NCI/DCP/GOCRG • Umar • 2013 Bertagnolli, et al., 2006

Adenoma Prevention with Celecoxib (APC)

0

10

20

30

40

50

60

70

Placebo200 mg BID

400 mg BID

All Adenomas

Advanced Adenomas

Bertagnolli, et al., N Engl J Med 2006; 355:873-884



Aspirin Versus Control on Risk of Death Due to Cancer (≥5 Years of Aspirin Treatment by Age at Randomization)

Ro

thw

ell e

t a

l., L

an

cet

20

11

: 37

7, 2

01

1


0.76

0.65

0.8

Colon Cancer Incidence

Colon Cancer Mortality

Aspirin and Colorectal Cancer Prevention [2° Analysis]

Relative Risk

0 1 2


P=0.35

P=0.005

P=0.02

5 Randomized Trials of Aspirin. Mean duration of treatment = 6 years

Rectal Cancer Incidence 0.9

P=0.58

Rectal Cancer Mortality

0.45

0.34

1.21

Proximal Colon Cancer Incidence

P=0.54

P=0.001

P=0.001

1.10

P=0.66

Proximal Colon Cancer Mortality

Distal Colon Cancer Incidence

Distal Colon Cancer Mortality

Rothwell et al., Lancet 2010. 376:1741


Colorectal Cancer Prevention Agents

Aspirin/

NSAIDs/

Curcumin/

Ca/VitD?

Aspirin/

NSAIDs

Aspirin/COXIBs/

NSAIDs/DFMO

Risk Effects Benefits

Hemorrhage Block Platelet Reduce risk of

aggregation thrombosis

Mask infection Reduce inflammation Treat inflammatory

arthritis/anti-cancer?

Mask tissue injury Reduce pain Treat pain

Impair wound healing Reduce proliferation Abnormal Control

of cell growth

Aspirin: Risk versus Benefits Anti-platelet

Anti-inflammatory

Reduces PGE2


Aspirin and Colorectal Cancer Prevention [2° Analysis]

Relative Risk

0 1 2


5 Randomized Trials of Aspirin. Mean duration of treatment = 6 years

Rothwell et al., Lancet 2010. 376:1741

1.01

0.81

0-2.9 years

3-4.9 years 0.7

>5 years

Major Extracranial Bleeds 1.95

1.37

0.63

0-2.9 years

3-4.9 years

>5 years

Cancer Incidence

Cross Trials Safety Analysis

• Over 16,000 patient-years of follow-up

• Pooled adjudicated analysis of six randomized trials comparing celecoxib to placebo

• Overall increase in cardiovascular risk identified

• Differences in risk based on the dose and

celecoxib dose-regimen

• Patients at highest baseline cardiovascular risk

had an increased relative risk for celecoxib-

related adverse cardiovascular events

Solomon et al., Circulation 2008

CTSA Trials

• Adenoma Prevention with Celecoxib (APC) Trial

• Prevention of Sporadic Adenomatous Polyps (PreSAP) trial

• Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT)

• MA-27 Breast Cancer Trial

• Celecoxib Diabetic Macular Edema (CDME) trial

• Celecoxib/Selenium Trial

3-category risk score, modified Framingham Risk model – Low: No known risk factor

– Moderate: One of following , age > 75, hypertension, hyperlipidemia, current smoker, low-dose ASA

– High: Diabetes, prior CV disease, or ≥ 2 risk factors in “moderate” category

Solomon et al. Circulation 2008

400qd

200 bid

400 bid

400 qd

200 bid

400 bid

400 qd

200 bid

400 bid

Low Risk

High Risk

400 qd

400 qd

200 bid

400 bid

High Risk 3.5 (1.9,6.4)

1.7 (0.9,3.2)

0.9 (0.3, 2.6)

2.3 (1.5, 3.4)

1.5 (1.2, 1.9)

1.4 (1.0, 2.2)

1.2 (1.0,1.5)

0.9 (0.4, 1.9)

1.0 (0.7, 1.4) 400qd

200 bid

400 bid

400 qd

200 bid

400 bid

400 qd

200 bid

400 bid

Low Risk

Moderate Risk

Hazard Ratio CV Death, MI, Stroke, HF or Thromboembolic Event

High Risk

400 qd

400 qd

200 bid

400 bid

High Risk

Baseline Risk – Dose Regimen Interaction p = 0.034 Solomon et al. Circulation 2008

3.5 (1.9,6.4)

HR (95% CI)

1.7 (0.9,3.2)

0.9 (0.3, 2.6)

2.3 (1.5, 3.4)

1.5 (1.2, 1.9)

1.4 (1.0, 2.2)

1.2 (1.0,1.5)

0.9 (0.4, 1.9)

1.0 (0.7, 1.4)

Pre-Rx CV Risk

Celecoxib Regimen and Baseline

Cardiovascular Risk: CTSA

6 7 5 4 3 2 1 0.3 0.4 0.5 0.6 0.8


PI: Richard Grimm, MD, Berman Center for Outcomes & Clinical Research, Hennepin Health Systems in Minneapolis Co-PI: John McNeil, MD, Monash University, Victoria Australia

N=19,0000 (16,000 in Australia, 3000 in US (minorities)

Hypothesis: Aspirin prolongs life, life free of dementia or life free of

significant physical disability in healthy participants aged ≥ 70 years (≥ 65 years for minorities)

Study Design: Prospective, randomized placebo-controlled

Agent: Aspirin 100 mg enteric-coated daily for 5 years

Primary endpoint: Composite: All-cause mortality, incident dementia or

permanent physical disability

Secondary Endpoints: All cause mortality Fatal and non-fatal cancers Fatal and non-fatal cardiovascular disease (CHD & stroke) Hospitalized heart failure, Sudden death, Dementia, Physical disability, Major hemorrhagic event

Status (Accrual): 12,000 as of March 2013

ASPirin in Reducing Events in Elderly (ASPREE)

• Aspirin is effective in reducing adenomas at 81/300yr1/300yr3/300

yr4/325 mg daily doses (17/27/21/72/5%)

• Celecoxib significantly reduced colorectal adenoma occurrence

(33/34%), advanced adenomas (57/51%)

• DFMO + sulindac is synergistic in preventing recurrent adenomas (70%)

• CV toxicity gives us a pause for NSAIDs and COXIBs in general population

• Role of Aspirin in cardioprotection and cancer prevention offers hope for

cancer prevention across most Gastrointestinal tract cancers

Summary:

Summary

Gastrointestinal Tract Cancer Prevention - CCCUPR 4-13-13.pdf · NCI/DCP/GOCRG • Umar • 2013...

Documents

Transcript of Gastrointestinal Tract Cancer Prevention - CCCUPR 4-13-13.pdf · NCI/DCP/GOCRG • Umar • 2013...