Download Chemoprevention of Cancer

Chemoprevention of Cancer:
An Update
WREN Convocation of Practices
May 9, 2009
Howard Bailey, MD
UWCCC Chemoprevention Program
Chemoprevention of Cancer
Definition
 Sporn (1976), use of drugs, biologics, or nutrients to
inhibit carcinogenesis
Rationale
 A 15% decrease in epithelial cancers would prevent
>100,000 deaths/yr and save $25 billion/yr
Background
 Epidemiology
 Geographic/cultural differences
 Genetics – 98% malignancies have somatic mutations rather
than germ line mutations
 association of infections with cancer
Chemoprevention of Cancer
 The study of carcinogenesis has led to the
current dogma that human carcinogenesis is a
multi-year process
 Boutwell RK, 1976; The biochemistry of pre-neoplasia
in mouse skin
 Frykberg and Bland, 1993; breast atypical hyperplasia
to DCIS to carcinoma may take 30 years
 Thus providing an opportunity to intervene
prior to accumulated mutations or phenotypic
changes
Basic Progression Model
T(0)
O’Shaughnessy, et al. - Clin Cancer Res 2002;8:314-46
10-30 years
Chemoprevention Clinical Trials
Phase II
Trial(s)
25-75
50-300
1-12
6-36
pK, dose, SEB mod.
safety
Phase III
Trials
300+
36-60
cancer inc.
Cost
Subjects (N)
Duration (months)
Primary Endpoints
Phase I
Trial
Risk
Candidate
Agent
Chemoprevention Drug Development
 How development differs from –
 Cancer Therapy
 Accepted surrogate of tumor/disease regression
 Primary goal can be determined relatively
quickly
 Vascular diseases
 More similar than cancer therapy
 Accepted surrogates
 Hypertension
 Hyperlipidemia
Chemoprevention Drug Development
 Similar to Vascular Health prevention, an
accepted surrogate marker/endpoint
would make chemoprevention drug
development more efficient.
 Intraepithelial Neoplasia?
 Colonic adenomas
 Cervical Carcinoma in situ
 Breast ductal carcinoma in situ
Intraepithelial Neoplasia
 Cancer and IEN frequently share phenotypic
and genotypic changes
 IEN is already considered a disease by many
and has led to the approval of multiple
interventions (celecoxib, diclofenac, topical
5FU, BCG, tamoxifen)
 Variability in diagnosis/interpretation
 Slow and relatively low rate of progression to
cancer
 Current complexity and limited understanding
Chemoprevention
 Phenotypic surrogates










Skin – actinic keratoses, dysplastic nevi
Oral – leukoplakia, erythroplakia
Lung – bronchial dysplasia
Esophagus – Barrett’s (dysplasia)
Breast – DCIS, LCIS, atypical hyperplasia
Colon – adenomas
Cervix – cervical intraepithelial neoplasia (CIN)
Endometrium – atypical hyperplasia
Prostate – prostatic intraepithelial neoplasia (PIN)
Bladder – superficial bladder cancer
Chemoprevention Agents –
Approved agents
 Tamoxifen
 Selective estrogen receptor modulator (SERM) for breast cancer
prevention
 NSABP – P1 study (Fischer et al. JNCI 90:1371, 1998), 7000
women in each arm (175 cancers in placebo, 89 cancers in Tam)
 Raloxifene
 Selective estrogen receptor modulator (SERM) for breast cancer
prevention
 NSABP – P2 (STAR) study,(Vogel et al. JAMA 295:2727, 2006),
approx 4000 post-menopausal women in each arm with an
expected BrCa rate of 4% over 5 years, observed only 0.4% in
each arm.
Chemoprevention Agents –
Approved agents
 Tamoxifen P1 study
Fisher JNCI 1998
Chemoprevention Agents –
Approved agents
 Tamoxifen P1 study
Chemoprevention Agents –
Approved Agents
 Tamoxifen and Raloxifene are approved
for women at “high risk”
 High risk is a women with a 1.66% chance of
developing invasive breast cancer in the next 5 years
 All women > 60 yo
 Younger women with some number of the following
risk factors: early menarche (<12 yo) , late
menopause (>55 yo), nulliparity or >30 yo at first
full term pregnancy, first degree family relative with
breast cancer, prior breast biopsies especially with
atypical ductal hyperplasia, …
Chemoprevention Agents –
Approved agents
Celocoxib
 Specific COX-2 inhibitor approved for adenoma
prevention in FAP (Steinbach et al. NEJM 342:1946,
2000)
 Prevention of sporadic polyps (Bertagnolli et al. NEJM
355:873, 2006)
 Increased cardiac risks (Solomon et al. NEJM
352:1071, 2005)
Sporadic Adenomas
Phase III Trials
APC Trial
• Sporadic CRN (n=2,035)
• 91 participating sites
• Celecoxib 200 mg bid or
400 mg bid vs. placebo
• Rec. adenomas at 3 years
AdvancedAdenomas
Adenomas
Recurrent
Placebo bid
*p<0.0001
vs. placebo; Bertagnolli – NEJM 2006;355:873-84
Celecoxib200 mg bid
Celecoxib400 mg bid
Chemoprevention Agents –
Approved Agents
 Quadravalent HPV vaccine for cervical cancer
 VLP vaccine against HPV 6, 11, 16, 18
 Initial Pilot study of monovalent (Koutsky et al.
NEJM 347:1645-51, 2002)
 Initial phase 2 quadravalent (Villa et al. Lancet
6:271-78, 2005)
 approved for females 9-26 yo
 FUTURE I an II studies (NEJM 356: 1915,
2007)
Chemoprevention Agents
 VLP vaccine, bivalent 16/18
 Harper et al. Lancet 367, 2006
 Further f/u on women who received all 3 doses
 Seropositivity/immunogenicity maintained for
≥ 5 yrs
 Protection beyond 16/18, also decreased 45/31
Chemoprevention Agents – Approved Agents
 Are they being used?
 Infrequently at best
 Reasons are many starting with limited interest
from Primary Providers and Lay Public’s negative
views
 Assessment of Dane County Providers
 M Jensen et al. survey of healthcare providers
for adolescents opinions regarding the HPV
vaccine.
 O Olaigbe et al. survey of healthcare providers
for women regarding tamoxifen for breast
cancer prevention
Prostate Cancer Prevention Trial
(PCPT): Specific Rationale

Link between androgens and CaP
 T 5-alpha-reductase DHT
AR
 Epidemiology
 Finasteride inhibits 5-alpha-reductase
 Safety profile from BPH studies
1993-96
18,882 Men
> 55 yrs, < 3
PSA,
normal DRE
2000-03
Endpoint: 7-year period prevalence of prostate cancer
Primary Endpoint:
Seven-Year Period Prevalence
Placebo
Finasteride
Known prostate cancer
status
4692
4368
Prostate cancer
1,147 (24.4%)
803 (18.4%)
Relative Risk Reduction 24.8% (18.6% - 30.6%), P < 0.001
Thompson, et al NEJM 2003
PCPT Conclusions
• Misclassification rates on biopsy were higher in
the placebo arm and high grade rate on
prostatectomies were not higher on finasteride
arm
• True risk of 8-10 is unknown
• Estimates based on PCPT data including
possibility of more high grade disease still show
significant overall health benefit (person-years
saved) to society with finasteride
• Use of 5α reductase inhibitors probably won’t
evolve unless another study is positive
Unger et al. Cancer 2005
Reduction by Dutasteride of
Prostate Cancer Events
(REDUCE)
• Dutasteride
– dual inhibitor of type 1 and 2 5α reductase
– BPH studies suggested decreased Pr CA incidence
– Serum DHT levels further reduced by dutasteride
• GSK sponsored study, 650 centers, 8000
subjects
• Men 50-75 yo, PSA 2.5-3.0 to 10 ng/ml, must
have a neg. prostate bx within 6 mos (no
HGPIN or ASAP), prostate volume ≤80 cc
Andriole et al. J Urology 2004
The Selenium and Vitamin E Cancer
Prevention Trial (SELECT)
• NCI sponsored prostate chemoprevention trial
opened 2001
– 32,000 men, ≥ 50-55 yo, PSA ≤4.0 ng/ml, DREnegative
– Selenomethionine 200 µg, α tocopherol 400 IU
– Followup every 6 mos
– Primary endpoints – Prostate Ca incidence
• Factorial design with 5 comparisons
• Each agent vs placebo, the combination vs placebo,
combination vs each agent
Lippman et al. JNCI 2005
SELECT
• Preliminary Results
• Neither Selenium or Vitamin E alone or
together prevented prostate cancer
• Uncertain findings –an increase in
prostate cancers in men taking Vit E
alone; and small increase in the number
of cases of adult onset diabetes in men
taking selenium
Chemoprevention Agents/Issues
with Micronutrients
 CARET, ATBC, and NPC Results
 Concerning negative results
 Micronutrients assumed not to be harmful
 Replacement doses vs supraphysiologic (prooxidant effects?)
 Regular dietary consumption vs
supplementation
 Smokers and gender differences in metabolism
Nutrients and Cancer
 Dietary Nutrients
 Polyphenols (primarily green tea)
 Strong epidemiologic data
 Important constituents are catechins (specifically
epigallocatechin gallate/EGCG)
 Cup of green tea contains 3-400 mg of polyphenols (10-30
mg EGCG)
 Encouraging clinical research at 400-800 mg of EGCG/day
 Isoflavones/Soy
 Phytoestrogen
 Genistein – UW bladder prevention study
Chemoprevention Agents - Genistein
Genistein inhibits growth of carcinoma cells of multiple tumor types in vitro.
It is a potent inhibitor of tyrosine kinase, a key enzyme in signal transduction.
Glycoside conjugates account for more than 2/3 of the total isoflavone content
of soybeans.
Nutrients and Cancer
 Dietary Nutrients (cont.)
 Carotenoids
  carotene
 Lycopene
– Polyphenolic constituent of tomatoes and some fruits
– How tomatoes are cooked/processed influences amount of
lycopene
– Epidemiologic studies
– Positive in vitro/in vivo effects
– Ongoing chemoprevention studies
 Lutein
 Organosulfurs/seleniums
 Anethole dithiolethione (ADT)
 Flavanoids
 Quercetin
Nutrients and Cancer
 Dietary Nutrients (cont.)




Curcumin
Perillyl alcohol
Resveratrol
Isothiocyanates/indoles
 Indole-3-carbinol/Diindolymethane (DIM)
 UW prostate study
 Phenylethyl isothiocyanate (PEITC)
Meta-analysis of Antioxidants for GI Cancer Prevention
Bjelakovic et al. Lancet 364:1219, 2004
Chemoprevention Development:
Directions?
 Better risk stratification
 Genomics, unbiased pursuit e.g. quantitative trait
loci
 Proteomics, a less invasive way to assess
intervention
 Non-invasive imaging of preneoplasia/intraepithelial
neoplasia
 Cross-disciplinary studies of health
maintenance, e.g. WHI
 WREN
 Wisconsin Network for Health Research (WiNHR)
Cancer Chemoprevention
• Possible study idea
• Green tea polyphenols in patients with or at
risk of metabolic syndrome
– Compelling data for beneficial effects of green
tea polyphenols in Cancer, CardioVascular and
Neurodegenerative disease and Insulin
resistance.
Chemoprevention of Cancer
 Clinical trials pose both new and old
issues for cancer-related drug
development
 We should look to other disciplines for
advice, e.g. renal or vascular preventive
health
 We need to “understand our audience
better”
Thank you.
Chemoprevention Agents
 Selenium Clinical studies
 NPC Trial
 1300 subj (Eastern U.S.) with skin CA hx
randomized to 200 g/d of selenized brewer’s
yeast or placebo (Duffield-Lillico et al. JNCI,
2003)
 Effects on skin cancer contradictory
 Significant decrease in prostate CA (Clark et al.
Br J Urol 89:730, 1998), but other cancer
incidence was examined also.
NPC Trial: Incidence and Relative Risk
of non-melanoma skin cancer
Baseline Se level
<105 ng/ml
105-122
>122
RR
0.87
1.49
1.59
P value
.42
.03
.01
Duffield-Lillico, JNCI, 2003
Chemoprevention / Development
 Clinical Testing
 Phase I testing
 normal volunteers vs increased risk population
 dose de-escalation or escalation
 randomization to one of multiple dose levels (for deescalation studies) or placebo
 Examples
 Phase I de-escalation study of DFMO, Love et al.
JNCI 85:732, 1993
 Phase I escalation study of UAB30, J. Kolesar et al.
 Phase Ib study of diindolymethane in subjects
undergoing prostatectomy, J Gee et al.
Chemoprevention / Development
 Clinical Testing
 Phase 2 testing
 2a – shorter duration (days to weeks) biomarker
studies
 2b – randomized, double-blinded, placebocontrolled longer duration (>3 mos) biomarker
studies
 Provide rationale for the design of a phase 3 study
 Examples
 Phase 2a study of genistein in subjects with
superficial bladder cancer, E Messing, & J. Gee
 Phase 2b study of DFMO in Organ Transplant
Recipients at risk of skin cancer,
Chemoprevention/Development
 Clinical Testing (cont.)
 Phase 3 – randomized, double-blinded,
placebo controlled studies
 Demonstrate a significant decrease in cancer
incidence or mortality or an accepted surrogate
 Validate surrogate markers
 Hopefully lead to improved population health
 Examples
 Phase 3 Study of DFMO in subjects with a history
of skin cancer
 Phase 3 Study of Tamoxifen in women at risk of
breast cancer
Phase III Trials
PreSAP Trial (n=1,561)
• 107 participating sites
• Celecoxib 400 mg qd
vs. placebo
• Rec. adenomas at 3
years
RR=0.64 (0.56-0.75);
any
RR=0.49 (0.33-0.73);
adv.
APPROVe Trial
(n=2,587)
• 108 participating sites
• Rofecoxib 25 mg qd vs.
placebo
• Rec. adenomas at 3
years
RR=0.76 (0.69-0.83);
any
RR=0.70 (0.57-0.73);
N Engl J Med 2006;355:885-95 and Gastroenterol 2006; epub
adv.
Cardiovascular Toxicity
Celecoxib
• APC Trial
• N=2,035 subjects
• Follow-up = 2.8-3.1 years
• CV deaths (%):
Rofecoxib
• APPROVe Trial
• N=2,586 subjects
• Follow-up = 3,327 pt-years
• CV Adverse events (%):
–Placebo (1%); RR=1.0
–200 mg BID (2.3%); RR=2.3
–400 mg BID (3.4%); RR=3.4
www.theoaklandpress.com;
www.washingtonpost.com;
4/7/05
12/18/04
N Engl J Med. 2005;352:1071-80
and 1092-102
–Placebo (2%); RR=1.0
–25 mg QD (3.6%); RR=1.9
Celecoxib and Colon Cancer Prevention
• Psaty and Potter (NEJM 355:950, 2006)
– Reviewed APC and PreSAP trials and concluded the
following
– Celecoxib decreases adenoma formation
– Celecoxib increases the risk of cardiovascular adverse
events
– The potential increase in CV event/mortality outweighs
the projected decrease in colon cancer incidence
• Could Celecoxib be an option in people with low
cardiac risk?
Gleason Score:
Percent of Men Evaluated
Percent of Men Evaluated
100%
Finasteride N = 4368
Placebo N = 4692
90%
80%
70%
60%
50%
1.25 RR
40%
30%
16.5%
20%
10%
10.5%
0.5%
1.2%
6.4%
5.1%
0%
2-4
5-6
Gleason Score
Not graded: Finasteride N = 46, Placebo N = 79
7 - 10
PCPT: Increased rate of High Grade
Cancers, Detection-bias?
•
•
•
•
The increase in HG was based on biopsies
RP is the gold-standard for determining GS
HG was not significantly increased at RP
Detection bias
– Increased PSA sensitivity
– Increased biopsy sensitivity
Lucia, et al JNCI September 2007
SIMULATED BIOPSY: Sampling Bias
Median Prostate
Volume:
38.8 cc
Placebo
vs
Finasteride
24.4 cc
(p = 0.001)
Lucia, et al, JNCI, 2007; 1375-83
Detection-bias: The Evidence
Bx findings in
GS 8-10 tumors
Finasteride
Placebo
(n=98)
mean sd
med
(n=61)
mean sd
med
38
20
33
43
25
40
Greatest lin extent (mm) 4.9
2.9
4.4
5.4
3.7
4.4
Aggregate lin ext (mm)
10.6
6.2
12.9
16.0
7.0
% cores pos
Bilateral disease
Perineural invasion
9.3
26.5%
9.2%
44.3%
(p=0.02)
16.4%
Lucia, et al JNCI September 2007
Number of Cancers
Does Finasteride Make the Grade?
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
1147
Finasteride = 4368
Placebo - 4692
803
776
457
190 184
90 53
20 55
Total
Cancers
2-4
5-6
Gleason Score
7
8 - 10
SELECT
• Selenium
– Essential cofactor for enzymatic processes,
e.g. redox
– Derived from diet, dietary levels related to
soil content
– Epidemiologic studies correlating low
selenium levels to increased prostate cancer
incidence
– Typical US diet contains 80-160 ug/d,
Recommended daily amount 55 ug/d
– Issues with form and optimum dose
DN Syed et al. Ca Epid Biom Prev 2007
Chemoprevention Agents
 Selenium Clinical studies
 NPC Trial
 1300 subj (Eastern U.S.) with skin CA hx
randomized to 200 g/d of selenized
brewer’s yeast or placebo (Duffield-Lillico
et al. JNCI, 2003)
 Effects on skin cancer contradictory
 Significant decrease in prostate CA (Clark
et al. Br J Urol 89:730, 1998), other
cancer incidence also reduced.
NPC Trial: Incidence and Relative Risk
of non-melanoma skin cancer
Baseline Se level
<105 ng/ml
105-122
>122
RR
0.87
1.49
1.59
P value
.42
.03
.01
Duffield-Lillico, JNCI, 2003
SELECT
• Vitamin E
– Naturally occuring compounds (tocopherols,
tocotrienes)
– Co-factor to many cellular functions, antioxidant effects
– Epidemiologic studies
– Typical US intake 10 mg/d, recommended is
15 mg/d
– Issues with form / dose
SELECT
• ATBC study
– Finnish study of 30,000 smokers randomized to α
tocopherol (50 mg), β carotene (20 mg)
– 30-40% decrease in prostate Ca, but 19% increase
in Lung Ca (more from β carotene)
• Prospective study from China of Vit E, Sel, β
carotene decreased prostate Ca
• Recent meta-analysis raised concerns for
increased CV events with vit E doses > 4001,000 IU/day
Chemoprevention Agents
under study at UW
• DFMO
• Vitamin D
– Because of use/indications outside of cancer
prevention, more extensively studied
• Others
– Genistein, Diindolymethane, Polyphenon E, Vitamin E
metabolites,
Examples by Target Organ
Kelloff, et al. - Cancer Epidemiol Biomarkers & Prev 2000;9:127-37
Chemoprevention Agents
O Olaigbe et al.




152 respondents out of approx 500 mailed
85% Physicians / 15% NP or PA
51% Fam Med, 26% Int Med, 14% Gyn
Knowledge of Tam and Breast Ca Prev
 7% very much, 75% basic, 18% very little
 Ever recommended Tam as preventive
 Yes 20%, No 80%
 Reasons for not recommending
 Hi risk/benefit ratio 23%, questionable effectiveness
20%, unpleasant side effects 10%, other 40%
Cancer Chemoprevention
Future Directions
• Better assessment of an individual’s risk
(via genomics or proteomics) will likely
lead to greater interest/willingness to
employ chemoprevention
• Consideration of more global health issues;
use of low risk/small gain agents which
modify risk of numerous serious illnesses