Preventive Oncology

Goals:

1. To identify the major carcinogens

that can reasonably be undermined.
2. To identify the major preventive
strategies that can reasonably be
implemented.
3. To identify the major screening
strategies that can reasonably be
implemented.

TABLE 4.1 - Level of Evidence for Smoking-Attributable Cancers

According to the United States Office of the Surgeon General
by Cancer Site and Yearly Smoking-Attributable Mortality - 2004
Cancer Site Yearly Smoking-Attributable Mortality

Evidence Sufficient to Infer Causal Relationship

Bladder 4,983
Cervix 447
Colon and rectumN/A
Esophagus 8,592
Kidney 3,043
Larynx 3,009
Leukemia (AML) 1,192
Liver N/A
Lung 125,522
Oral cavity and pharynx 4,893
Pancreas 6,683
Stomach 2,484

Evidence Suggestive but Not Sufficient to Infer Causal Relationship

Breast

Inadequate to Infer Presence or Absence of Causal Relationship

Ovary

Evidence Sufficient to Infer No Causal Relationship

Prostate

The Surgeon General vs.

the Marlboro Man: Who
Really Won?

ByAlan Blum, MD
The images in this slide set are from an exhibition
curated by Alan Blum, MD, at the University of
Alabama Gorgas Library (November to December
2013) to commemorate the 50th anniversary of the
Surgeon Generals Report on Smoking and Health,
released on January 11, 1964 by Dr. Luther Terry.
See
more
at:
http
://www.consultantlive.com/atrial-fibrillation/s
urgeon-general-vs-marlboro-man-who-really-won?G
UID=51F950F2-03E8-4052-8E97-C1C08B74F6AB&XGUID
&
rememberme=1&ts=23122014#sthash.xWUWdJXC.
dpuf

Select Treatment Strategies Used for Tobacco Cessation

Treatments
Provide and monitor the use of nicotine replacement or other
pharmacotherapy.
Provide education regarding the health effects of tobacco use and its
addictive and relapsing nature.
Identify and change environmental and psychological cues for
tobacco use.
Generate alternative behaviors for tobacco use.
Assist in optimization of social support for cessation efforts and
address tobacco use in family members.
Prevent relapse including the identification of future high-risk
situations and plans for specific behaviors in those situations.
Provide motivational interventions as needed throughout treatment.
Identify relaxation techniques such as guided imagery and
progressive muscle relaxation.
Provide behavioral strategies to address depressed mood (e.g.,
increasing pleasurable activities).
Provide crisis intervention including appropriate referrals and
emergency intervention if indicated.

First-Line Pharmacotherapy Agents for the Treatment of Nicotine

Dependence

Agent
Nicotine Replacement
Transdermal (patches)

Dose

Mechanism

16 h or 24 h
7, 14, or 21 mg
1 patch/d

Steady state NRT to reduce 610 CPD: 14 mg daily

craving and withdrawal
8 wks then 7 mg daily 2
wks
>10 CPD: 21 mg daily 6
wks, then 14 mg 2 wks,
then 7 mg 2 wks

Gum

2 or 4 mg
Max: 24 pieces/d

Short-term NRT to reduce

craving and withdrawal

First cigarette >30 min

after waking: 2 mg PO q12
hr
First cigarette <30 min
after waking: 4 mg PO q12
hr

Lozenge

2 or 4 mg
Max: 20 lozenges/d

Short-term NRT to reduce

craving and withdrawal

1st cigarette >30 min

after waking: 2 mg PO q12
hr
1st cigarette <30 min
after waking: 4 mg PO q12
hr

Nasal spray

0.5 mg/spray
Max:10 sprays/hr or 80
sprays/d
4 mg/cartridge
Max: 16 cartridges/d

Short-term NRT to reduce

craving and withdrawal

1 spray/nostril q15 hr

Short-term NRT to reduce

craving and withdrawal

1 cartridge inhaled over 20

min q1.56 hr

Bupropion (Zyban)

150 mg

Block nicotinic receptors

and reduces reward

Varenicline (Chantix)

0.5 or 1 mg

Dopaminergic reward and

partial nicotinic receptor
antagonist

1 tablet daily 3 d, then 1

tablet twice daily for 712
wks
0.5 mg daily 3 d, then
0.5 mg twice daily 3 d,
then 1 mg twice daily

Inhaler

Use

Section 1: Etiology of Cancer

Chapter 4: Tobacco
Chapter 5: Oncogenic Viruses
Chapter 6: Inflammation
Chapter 7: Chemical Factors
Chapter 8: Physical Factors
Chapter 9: Dietary Factors
Chapter 10: Obesity and Physical Acti
vity

Chapter 5: Oncogenic Viruses

Oncogenic viruses are important causes of
cancer, especially in less industrialized countries
and in immunosuppressed individuals.
They are common causes of lymphomas, and
anogenital, oral, and hepatocellular carcinomas
and are associated with a variety of other
malignancies.
Vaccines and antiviral agents play an important
role in the prevention of virus-induced cancers.
Studies of virus pathogenesis will continue to
establish paradigms that are critical to our
understanding of cancer etiology in general.

Oncogenic Viruses
Lymphomas
Epstein-Barr virus
Kaposis sarcoma herpesvirus
Merkel cell polyomavirus
Human T-cell leukemia virus
Anogenital & Oral carcinomas
Papillomavirus **
hepatocellular carcinoma
Hepatitis B virus *
Hepatitis C virus *

Treatment *
Hepatitis B virus
alpha
interferon
or
nucleos(t)ide
analogs
that
inhibit
the
viral
polymerase, such as lamivudine,
telbivudine, entecavir, adefovir, and
tenofovir.
Hepatitis C virus
24 to 48 weeks of pegylated IFN- and
ribavirin

Vaccine - Papillomavirus

Two preventive vaccines against cancer-causing

HPVs, Gardasil (Merck) and Cervarix (GSK), may
confer lifelong immunity.
Both vaccines cover HPV16 and HPV18 which,
together, cause about 70% of all cases of
cervical cancer worldwide.
Gardasil also includes VLPs based on HPV types
6 and 11, which rarely cause cervical cancer but
together cause about 90% of all genital warts.
Large prevention clinical trials targeting the
most prevalent HPV types in different regions of
the world are warranted.

Vaccine - Papillomavirus
Questions such as the necessity of repeat vaccinations and the
longevity of protection from an HPV infection remain to be
determined. It is estimated that if women were vaccinated against all
high-risk types of HPV before they become sexually active, there
should be a reduction of at least 85% in the risk of cervical cancer
and a decline of 44% to 70% in the frequency of abnormal
Papanicolaou (Pap) smears attributable to HPV.
Unfortunately, even after vaccination is implemented, a reduction in
the incidence of cervical cancer could not be expected to become
apparent for at least a decade. Therefore, therapeutic vaccines are
still very much needed to reduce the morbidity and mortality
associated with cervical cancer.
The therapeutic approach to patients with preinvasive and invasive
cervical cancers is to develop vaccine strategies that induce specific
CD8+ cytotoxic T-lymphocyte responses aimed at eliminating virusinfected or transformed cells. Early-phase human trials using
therapeutic vaccines have shown that they are safe; no serious
adverse effects have been reported.

Chapter 6: Inflammation
Almost 50% of all cancers can be prevented based
on what we know today. All the studies summarized
previously suggest that inflammation is closely
linked to cancer, and the incidence of most cancers
can be reduced by controlling inflammation.
Proinflammatory conditions such as colitis,
bronchitis, hepatitis, and gastritis can all eventually
lead to cancer. Thus, one must find ways to treat
these conditions before the appearance of cancer.
All these studies indicate that an anti-inflammatory
lifestyle could play an important role in both the
prevention and treatment of cancer.

Chapter 7: Chemical Factors

For common cancers, nongenetic risk
factors are dominant, and the best
associations for genetic risks of sporadic
cancers indicate that the risks for specific
genetic traits are typically less than 1.5fold.
The role of the tumor microenvironment,
the cancer stem cells, and feedback
signaling to and from the tumor also have
been recently recognized as important
contributors to carcinogenesis, although

Chapter 8: Physical Fac

Losstors
or defects in theATMorp53genes result

in
abrogation
of
radiation-induced
cell
cycle
checkpoints, which manifests itself as the highly
cancer-prone human syndromes ataxia telangiectasia
or Li-Fraumeni, respectively.
The major sensor of radiation-induced damage in
cells is the ataxia-telangiectasia mutated (ATM)
kinase.
The kinase p53 regulates the gene expression of
specific genes such asp21, which inhibits cyclindependent kinase (CDK)2- and CDK4-mediated
phosphorylation of the retinoblastoma protein,
resulting in a block in the progression from the
G1phase to the S phase of the cell cycle.

Skin Cancer
The incidence of sun-induced skin cancer,
especially melanoma, is on the increase due to
higher rates of sun exposure in the general
population.
The link between UV light exposure and skin cancer
is very strong, but the role of UV light in the
etiology of nonmelanoma and melanoma skin
cancer differs.
Although the risk of nonmelanoma cancer relates to
the cumulative lifetime exposure to UV light, the
risk of contracting melanoma appears to be linked
to high sunlight exposure during childhood.

Ionizing Radiation
Twenty
years
after
Hiroshima/Nagasaki,
significant increases in the incidence of thyroid
cancer and leukemia were observed; however, it
took almost 50 years before solid tumors
appeared in the population as a result of radiation
exposure from the atomic bombs.
Radon is the second leading cause of lung cancer
in the United States.
There is a growing concern about the dramatically
increased use of whole body CT scans for
diagnostic purposes.
Cancer patients who receive radiation therapy are
at risk of developing secondary tumors induced
by the radiation therapy treatment.

Cancer Prevention: The Roles of Diet and Chemoprevention

Peter Greenwald, M.D., Dr.P.H., and Sharon S. McDonald, M.S.
Considerable evidence links dietary factors with cancer risk, but ongoing
investigation is needed.
Background: Reduction of cancer risk by either preventing carcinogenesis or
stopping carcinogenesis in its early stages is a logical approach for reducing
the cancer burden, both for high-risk individuals and for the general
population. The areas of dietary modification and chemoprevention show
considerable promise as effective approaches for cancer prevention and are a
focus of research efforts.
Results: Diet and cancer studies show that, generally, vegetables and fruits,
dietary fiber, and certain nutrients seem to be protective against cancer,
whereas fat, excessive calories, and alcohol seem to increase cancer risk.
Chemoprevention research is closely linked to diet and cancer research and
represents a logical research progression.
Conclusions: Dietary epidemiologic studies have helped to identify many
naturally occurring chemopreventive agents. Currently, randomized clinical
prevention trials sponsored by the NCI include dietary interventions (e.g.,
low-fat and/or high-fiber vegetables and fruits) targeting breast and
colorectal cancer, chemoprevention trials using micronutrients (e.g., vitamin
E, calcium, vitamin D) aimed at lung and colorectal cancer, and

Doll and Peto claim that approximately

30% to 40% of cancers may be avoidable
with changes in nutrition; however, much
of this risk of cancer is related to being
overweight and to inactivity.
Excessive energy intake and lack of
physical activity, marked by rapid growth in
childhood and being overweight, have
become growing threats to population
health and are important contributors to
risks of many cancers.
Nevertheless, the cumulative incidence for
many cancers has decreased over the past
decade, in part due to the decreasing

Strength of the Observational Epidemiologic Evidence

for Physical Activity as a Protective Factor and Obesity as a Risk
Factor
for Cancer, By Type of Cancer

Physical Activity Overweight/Obesity

Breast, postmenopausal +++
+++
Breast, premenopausal ++
++ (protection)
Colon
+++
+++
Endometrium
+
+++
Esophagus, adenocarcinoma ?
+++
Kidney/renal cell
?
+++
Gallbladder
?
++
Pancreas
?
+++
Non-Hodgkin lymphoma ?
+
Prostate, aggressive
+
+
Lung
+
?
Ovary
?
?

Prophylactic Surgery
Since the heritable component of some cancer predispositions has been
linked to mutations in specific genes, clinical interventions have been
formulated for mutation carriers within affected families.
The primary interventions for mutation carriers for highly penetrant
syndromes, such as multiple endocrine neoplasia (MEN), familial
adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer
(CRC), and hereditary breast and ovarian cancer syndromes, are primarily
surgical.
This chapter addresses breast, gastric, ovarian and endometrial, and MENs
and colorectal. For each, the clinical and genetic indications and timing of
prophylactic surgery and its efficacy, when known, are provided.
Prophylactic surgery in hereditary cancer is a complex process, requiring a
clear understanding of the natural history of the disease and variance of
penetrance, a realistic appreciation of the potential benefit and consequence
of a risk-reducing procedure in an otherwise potentially healthy individual,
and the long-term sequelae of such surgical intervention, as well as the
individual patients and familys perception of surgical risk and anticipated

Micronutrients
Certain agents, including the retinoids, beta-carotene,
folic acid, calcium plus vitamin D, vitamin E, and
selenium, have received substantial attention for a
possible role in reducing the risk of cancer in humans.
Some trials have observed statistically significant
reductions in the risk of the primary end point (e.g.,
retinoids in skin carcinogenesis models, calcium in
colorectal adenomas, antioxidant nutrients in Linxian,
China, for gastric cancer prevention).
Other trials have observed statistically significant
increases in the risk of the primary end points (betacarotene and retinoid lung cancer prevention trials in
smokers, vitamin E and prostate cancer, selenium and
nonmelanoma skin cancer).

Anti-Inflammatory Agents
Given the 10-year latency between adenoma formation and a cancer
event, prospective trials sufficiently powered to detect colorectal
cancer incidence end points are unlikely in the future. The U.S.
Preventive Services Task Force (USPSTF) does not recommend the
use of aspirin or NSAIDs as cancer riskreducing agents for normal
risk populations.
Minimal prospective cancer risk reduction data are available at other
epithelial organ sites. Ketorolac, given as a 1% rinse solution, did not
reduce the size or histology of leukoplakia lesions.
Celecoxib reduces the Ki67 labeling index and increases the
expression of nuclear survivin without significantly changing the
cytoplasmic survivin in bronchial biopsies of smokers.
Cancer prevention trials of aspirin as interventions for delaying
progression from intraepithelial neoplasias in other epithelial sites
remain ongoing for the lower esophagus.
No prospective, randomized trials or data are available for breast,

Selective Estrogen Receptor Modulators - Concepts

SERMs function as estrogen receptor (ER) agonists and
antagonists depending on the SERM structure and target
tissue. Predominant ER receptors occur in the human
uterus, cortical bone, and the liver; whereas predominant
ER receptors occur in blood vessels, cancellous bone,
the whole brain, and immune cells.
During carcinogenesis, the amount of ER increases while
the amount of ER decreases in breast tissues.
Ideally, a desirable SERM for cancer prevention will
function as an antiestrogen in the breast and uterus, but a
partial estrogen agonist in skeletal, cardiovascular,
central nervous system (CNS), GI tract, and vaginal
tissues.

Selective Estrogen Receptor Modulators - Efficacy

Despite the widespread evidence of breast cancer
preventive efficacy for tamoxifen and raloxifene, only 3%
to 20% of eligible high-risk women agree to take
tamoxifen for primary prevention.
Although aromatase inhibitors may have a more favorable
risk to benefit profile than SERMs, long-term outcomes
and toxicity experience for aromatase inhibitor riskreducing agent intervention are not available to date.
In the National Surgical Adjuvant Breast and Bowel
Project, tamoxifen-treated women with aBRCA2mutation
but not aBRCA1mutation had reduced cancer incidence,
but subsequent data from another group have found
reduced cancer risk in women with both BRCA mutations.
Data remain insufficient to recommend the use of SERMs

Carcinogenesis
Carcinogenesis can be divided conceptually into four steps: tumor
initiation, tumor promotion, malignant conversion, and tumor
progression.
DNA adduct formation that causes either the activation of a protooncogene or the inactivation of a tumor-suppressor gene can be
categorized as a tumor-initiating event.
Tumor promotion comprises the selective clonal expansion of initiated
cells.
Malignant conversion is the transformation of a preneoplastic cell into
one that expresses the malignant phenotype.
Tumor progression comprises the expression of the malignant
phenotype and the tendency of malignant cells to acquire more
aggressive characteristics over time.
--Holland-Frei, Cancer Medicine. 6th edition.

Prostate Cancer
Finasteride [Proscar], a selective, competitive inhibitor of
type 2 5-steroid reductase, inhibits proliferation in the
transformed prostate cell.
Finasteride appears to be more effective in the promotion
phase of prostate carcinogenesis; use of finasteride for
seven years reduced the incidence of prostate cancer, but
it did not significantly affect mortality.
Dutasteride [Avodart] inhibits both 5-steroid reductase
inhibitor types 1 and 2 isoforms and has similar
anticarcinogenesis activity in preclinical models to
finasteride.
Finasteride and dutasteride reduce the incidence of

Signal Transduction Modifiers - 1

Difluoromethylornithine (DFMO) is an enzymeactivated irreversible inhibitor of ornithine decarboxylase
(which is transactivated by thec-MYC oncogene and
cooperates
with
theRASoncogene
in
malignant
transformation).
Topical-DFMO caused regression of cervical intraepithelial
neoplasia.
DFMO has anticarcinogenic activity for nonmelanoma skin
cancers, primarily basal cell carcinoma.
In combination with an NSAID (sulindac), DFMO reduced
adenoma recurrences, suggesting a synergistic reduction
of colorectal cancer risk.

Signal Transduction Modifiers - 2

Metformin reduced the risk of solid tumors by 25% to
30%; there was a lower incidence of invasive breast
cancer in metformin-treated women with type 2 diabetes
mellitus.
No natural products have been studied in large
prospective, cancer incidence riskreduction trials.
Statins and Bisphosphonates are still being studied.
Multi-agent approaches are being conceptualized.

Anti-Infectives
Infectious agents that cause cancer include: Helicobacter
pylorifor gastric adenocarcinoma; the human hepatitis
viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV)
for hepatocellular carcinoma;human papilloma viruses
(HPV) for cervical, anal, vulva, penis, and oral cavity and
pharynx carcinomas; herpes virus-8 for Kaposi sarcoma;
Epstein-Barr virus for Burkitt and other lymphomas; liver
flukes for cholangiocarcinoma; and schistosomes for
bladder carcinoma.
The success of the HPV vaccine at reducing the incidence
of intraepithelial neoplasia of the cervix examplifies the
potential of immuno-chemoprevention for epithelial
targets for which an etiologic agent can be identified.

Helicobacter pylori
Intestinal-type gastric adenocarcinoma arises through a
multistep process: chronic gastritis initiated byH. pylori
[whichinfects 50% of the worlds population] gastric
mucosal atrophy intestinal metaplasia dysplasia
adenocarcinoma. Infection withH. pyloriis associated
with an OR of 2.7 to 6.0 for gastric cancer;CagAincreases
this risk by 20- to 40-fold; the risk of developing gastric
adenocarcinoma with anH. pyloriinfection is estimated to
be 1% to 3%.
Eradication ofH. pyloriwith antibiotics and antiinflammatory
agentsfor
example,
amoxicillin,
metronidazole, and bismuth subsalicylateincreases the
rate of regression of nonmetaplastic gastric atrophy and
intestinal metaplasia in geographically diverse regions.