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Preventive Oncology - 2

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.
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
“Out-takes” Derivative of Prior Presentation

Topics Covered with Specificity:
• Screening [CME]
• Tobacco [E-Cigs]

Topics Covered Generically:
• Oncogenic Viruses
• Chemical Carcinogens
• Diet

• Flip Focus [Tobacco ←→ Cancer Control]
• Original Research re: Anti-Tobacco World
Screening [CME]
Lung, colorectal, breast, and prostate cancer are the leading
causes of cancer-related deaths in the United States. Together,
these cancers accounted for an estimated 46% of all cancer-
related deaths, or more than 273,000 deaths, in 2016. This course
provides an overview of the major issues in cancer screening,
appropriate adherence to guidelines and barriers to adherence,
controversies regarding guideline criteria, and the effect of
screening on mortality. Also included are detailed
recommendations for the five major cancer types for which
guidelines on screening and counseling have been developed:
breast, cervical, colorectal, lung, and prostate cancers.
Recommendations for other cancers of concern are included as
well. Lastly, strategies to enhance cancer screening are also
91991 Cancer Sc 10 AMA PRA $40 Add
Colorectal Cancer Screening in the
United States: What Is the Best FIT?

In the United States, colorectal cancer (CRC) incidence and mortality have declined by roughly 3% per
year since 2001 (1). Screening probably explains much of this public health success; however, the
optimal method for it remains unclear. Colonoscopy accounts for at least 60% of all CRC screening in the
United States, despite its greater expense and risk for complications compared with other options (2).
Surprisingly little published evidence supports the predominance of colonoscopy. Unlike for fecal occult
blood testing or flexible sigmoidoscopy, no controlled studies have shown that colonoscopy reduces CRC
incidence or mortality. Most studies have reported that the cost-effectiveness of other CRC screening
methods equals or exceeds that of colonoscopy (3). Recently, the clinical effectiveness of screening
colonoscopy itself came under fire, with several studies showing excellent protection against left-sided
CRC but far less against right-sided disease (4). Long-awaited trials comparing colonoscopy with stool
blood–based screening methods are under way, but informative results will not be available for years.
In 1682, Giovanni Battista
Morgagni demonstrated the
absolute necessity of
basing diagnosis, prognosis, and
treatment on an exact and
comprehensive knowledge of
anatomical conditions.
Peter Greenwald, MD, DrPH

• NCI’s Associate Director for Cancer Prevention
Division of Cancer Prevention and Control.

• Started the American Stop Smoking Intervention Study
(ASSIST) and the “5 A Day” nutritional program in
partnership with industry and the private sector.

• Started a community clinical oncology network that
spawned the Breast Cancer Prevention Trial (Tamoxifen
halved breast cancer incidence in high-risk women) and
the Prostate Cancer Prevention Trial (Finasteride
quartered prostate cancer incidence).
Levels of Evidence
• Cancer Screening, Prevention and Treatment
studies can be ranked by noting the strength of
the study-design and endpoint-data.

• Five requirements should be met before
Screening for a particular medical condition as
part of routine medical practice; comparable
scales apply to Prevention and Treatment.

• Endpoints may relate to Incidence, Mortality, or
an Intermediate-Point.
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
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
Epstein-Barr virus
Kaposi’s 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
• Hepatitis C virus
• 24-48 weeks of pegylated IFN-α and
Agent Orange → Dioxin →
Immunosuppression → HPV
You were a 69-year-old man when you noticed development of
a solitary left-neck mass on 4/7/2016….You stopped smoking
cigarettes (after unknown pack-years) in 2003. Examination
was normal, except for both matted left anterior inferior neck
nodes and a 2 cm.2 area of palpable induration on the left side
of the posterior tongue. Initially/subsequently, you have had no
major problem eating/drinking.

On 6/6/2016, the biopsy showed epidermoid/squamous-cell
carcinoma; it was well-differentiated, was dysplastic with in-situ
carcinoma (KI-67) features, and was positive for P-16 (HPV-16).

…It was not uncommon to have to ford small rivers and
streams that were covered with what seemed to us to be AV
gas or other fuel-smelling substances. As field Infantry, it was
rarely possible to clean either yourself or your clothes and gear
of these smelly fluids. It was standard procedure for us to
patrol in and around these areas 4-5 days a week. This went on
We found that exposure to HPV-16 increased the association with
oropharyngeal cancer regardless of tobacco and alcohol use, but we
uncovered no evidence of synergy between exposure to HPV-16 and
tobacco or alcohol use. For these reasons, our data suggest two distinct
pathways for the development of oropharyngeal cancer: one driven
predominantly by the carcinogenic effects of tobacco or alcohol (or both)
and another by HPV-16-induced genomic instability….Therefore, tobacco
and alcohol were important risk factors for oropharyngeal cancer, but they
may not have acted as cofactors in HPV-mediated carcinogenesis in the

{D'Souza G, et al. Case-Control Study of Human Papillomavirus and
Oropharyngeal Cancer. N Engl J Med. 2007;356(19):1944-56. NEJMoa065497#t=article}
Basic Science and Clinical Literature

linking HPV-16 and OSSC
immunotoxicity of Dioxins
immune defects linked to Dioxin
immune defects linked to AO [and HPV-16]
immunotoxicity linked to AO [and Dioxin]
longevity of the AO-exposure
high prevalence of HPV-16
potential to invoke HPV-16 prognostically
Schecter A., Poiesz B., Brandt-Rauf P., Rapke O., Ball M. Med Sci Res 19:273 (1991).
Ngaon L., Yoshimura T. Asian Pac J Cancer Prev 2:199 (2001).
Butel J.S. Carcinogenesis 21:405 (2000).
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 68:69 (1997).
Pokrovsky A., Chernykh A., Yastrebova O, Tsyrlov I.B. Biochem Biophys Res
Commun 79:46 (1991).
Tsyrlov I.B., Pokrovsky A. Xenobiotica 23:457 (1993).
Zacharevsky T.K. In: Toxicology in Silico 1:11 (2002).
Wu J., Shur I.N, Tsyrlov I.B. Organohalogen Compounds 70:1471 (2008).
Murayama T., Inoue M., Mori S., Eizuru Y. Biochem Biophys Res Commun 296:651
Cinatl J., Vogel J., Kotchetkov R., Wilhelm A., Doerr H. FEMS Microbiol Rev 28:59
Diliberto J., DeVito M., Ross D., Birnbaum L Toxicol Sci 61:241 (2001).
Kasai A., Hiramatsu N., Meng Y., Yao J., Maeda S., Kitamura M. Anal Biochem
337:84 (2005).
Therefore, specifically and generally, AO-exposure was a substantial
contributing factor to development of a respiratory-tract cancer
located at the tongue-base, OSCC, due to its having caused immuno-
suppression and subsequent HPV-16 infection (given the presence of
HPV-16 on biopsy); thus, because there is no evidence that
tobacco/alcohol played any pathogenic role in the etiology of OSCC,
support for this conclusion is generated both by noting positive features
(HPV-16) and rejecting any potential negative features (behavioral). No
article in the medical literature undermines this viewpoint, and it is not
merely “speculative” to have drawn these definitive, indubitable
conclusions. This is not only based upon the preponderance [indeed, “all”]
of the evidence, but it is also not merely “presumptive.” One more point is
in-order: sometimes, an expert will be called-upon to claim linkage of an
environmental concern and the development of a medical disorder and
may be tempted to confirm such an association without having conveyed
a reasonable basis for having done so. This is not the situation in this
case, for all information has been assessed from a “disinterested”
perspective, notwithstanding the fact that this physician has been an anti-
tobacco super-activist since the late 1970’s. If anything is unclear, please
so advise.
Vaccine – Papillomavirus **

•Two preventive vaccines against cancer-causing HPVs,
Gardasil (Merck) and Cervarix (GSK), may confer lifelong

•Both vaccines cover HPV16 and HPV18 which, together,
cause about 70% of all cases of cervical cancer

•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
Vaccine -
•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 virus-
infected 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

•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.
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 risk–reducing 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,

•Infectious agents that cause cancer include: Helicobacter
pylori for 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 by H. pylori
[which infects 50% of the world’s population] → gastric
mucosal atrophy → intestinal metaplasia → dysplasia →
adenocarcinoma. Infection with H. pylori is associated
with an OR of 2.7 to 6.0 for gastric cancer; CagA increases
this risk by 20- to 40-fold; the risk of developing gastric
adenocarcinoma with an H. pylori infection is estimated to
be 1% to 3%.

•Eradication of H. pylori with antibiotics and anti-
inflammatory agents—for example, amoxicillin,
metronidazole, and bismuth subsalicylate—increases the
rate of regression of nonmetaplastic gastric atrophy and
intestinal metaplasia in geographically diverse regions.
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 1.5-

• 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
Chapter 8: Physical
•Loss or defects in the ATM or p53 genes result in
abrogation of radiation-induced cell cycle checkpoints,
which manifests itself as the highly cancer-prone human
syndromes ataxia telangiectasia or Li-Fraumeni,

•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 as p21, which inhibits cyclin-dependent
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
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 America; radiofrequency and microwave
radiation are not carcinogens.

•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
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
• 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.
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
•Certain agents, including 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 (beta-
carotene and retinoid lung cancer prevention trials in
smokers, vitamin E and prostate cancer, selenium and
nonmelanoma skin cancer).
• Doll and Peto claimed 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

• 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
prevalence of smoking and use of hormone therapy.
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 ? ?
Tobacco as a Carcinogen
• The International Agency for Research on
Cancer (IARC) classified cigarette smoke
and smokeless tobacco as Group 1

• IARC has also identified 72 measurable
carcinogens in cigarette smoke where
evidence is sufficient to classify them as
Group 1 (carcinogenic to humans), 2A
(probably carcinogenic to humans), or 2B
(possibly carcinogenic to humans).
The Surgeon General vs. the Marlboro
Man: Who Really Won?
• Alan Blum, M.D., curated an exhibition
at the University of Alabama
commemorating the 50th anniversary
of the Surgeon General’s Report on
Smoking and Health [January 11,
1964] by Luther Terry, M.D.
Tobacco and Public Health

• EGFRm NSCLC patients derived significant PFS
benefit from TKI over chemotherapy regardless of
smoking status, but the PFS benefit from EGFR TKIs
over chemotherapy is significantly higher in never-
smokers than ever-smokers by meta-regression

• The Federal Aviation Administration is warning
airlines about fire risks from electronic cigarettes
stored in checked luggage and is recommending
that passengers bring them into the cabins instead.
Tobacco and Public
• “Uptown. The place. The taste.”
• "Uptown—The Disgrace.“

• Snus
• Naswār
• Chew
• Dip
• The increase in adenocarcinoma of the lung
observed in the United States over recent
decades may reflect changes made to the
cigarette, such as filters, filter ventilation, and
tobacco-specific nitrosamines (TSNA) in smoke
produced by the relatively high amount of burley
tobacco used in the typical US cigarette blend.

• The increasing incidence of lung cancer may be
due to radioactive polonium in cigarettes.
Aryl Hydrocarbon
• The normal white population in the United States can be
divided into three separate groups having low,
intermediate, and high inducible aryl hydrocarbon
hydroxylase activities, with frequencies of 44.7 per cent,
45.9 per cent and 9.4 per cent respectively.

• Fifty patients with bronchogenic carcinoma were studied,
and the frequencies of the three groups were 4.0 per
cent, 66.0 per cent and 30.0 per cent respectively.

• Whether the higher AHH levels are the cause or the
result of the primary lung cancer is unclear.
Smoking Topography
• Scientific study of this “elastic”
process is affected by the number of
puffs, puff size, frequency, duration,
and velocity.

• Tobacco may [or may not] be a
Precipitating Factor in Angina
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
Tobacco Control
• There is a causal relationship between cigarette smoking and
adverse health outcomes; quitting smoking improves the
prognosis of cancer patients.

• There is a causal relationship between cigarette smoking and
increased all-cause mortality and cancer-specific mortality.

• There is a causal relationship between cigarette smoking and
increased risk for second primary cancers known to be caused
by cigarette smoking, such as lung cancer.

• There is suggestive evidence (insufficient to infer causation)
that cigarette smoking increases treatment-related toxicity and
mortality (risk of recurrence and poorer response to treatment).
Decreases Risk
• Some effects of “current” smoking are distinct from an “ever”
or “former” smoking history; many effects of smoking are

• The adverse effects of smoking and the benefits of cessation
may have been under-reported because 30% of cancer
patients who smoke deny tobacco use; this reflects a potential
discrepancy between the effects of smoking based on
subjective versus biochemically-confirmed assessments.

• Complications may arise post-operatively, may preferentially
affect the lungs, may enhance XRT-toxicity, may worsen
mucositis, may yield more hospitalizations, and may even yield
ongoing vasomotor symptoms.
Smoking Affects Treatment
• Head and neck cancers that are human papilloma
virus (HPV) positive are known to have an improved
prognosis as compared with HPV-negative tumors.

• Light or never smokers have a higher rate of EGFR-
positive lung tumors that may respond to biologic
therapy using EGFR tyrosine–kinase inhibitors. {EGFR
= Epidermal Growth Factor Receptor}

• Smokers may be better served with conventional
cancer treatments rather than these biologic
• Use an ongoing SOAP-model, emphasizing the need
to reformulate data.
• Tools abound [ALA, ACS, NCI, ASCO].
• Most smokers are unsuccessful in their attempts to
quit smoking; the most effective evidence-based
treatments increase the odds of quitting by 3-times,
with 12-month cessation rates of approximately
40% relative to placebo.
• Low-tar cigarettes (as compared to full-
flavor varieties) afford neither an individual nor a
public health benefit, per both laboratory-based and
epidemiologic studies.
Select Treatment Strategies Used for Tobacco Cessation

• Provide and monitor the use of nicotine replacement or other
• 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 Dose Mechanism Use
Nicotine Replacement
Transdermal (patches) •  16 h or 24 h Steady state NRT to reduce •  6–10 CPD: 14 mg daily ×
• 7, 14, or 21 mg craving and withdrawal 8 wks then 7 mg daily × 2
• 1 patch/d wks
• >10 CPD: 21 mg daily × 6
wks, then 14 mg × 2 wks,
then 7 mg × 2 wks
Gum •  2 or 4 mg Short-term NRT to reduce •  First cigarette >30 min
• Max: 24 pieces/d craving and withdrawal after waking: 2 mg PO q1–2
• First cigarette <30 min
after waking: 4 mg PO q1–2
Lozenge •  2 or 4 mg Short-term NRT to reduce •  1st cigarette >30 min
• Max: 20 lozenges/d craving and withdrawal after waking: 2 mg PO q1–2
• 1st cigarette <30 min
after waking: 4 mg PO q1–2
Nasal spray •  0.5 mg/spray Short-term NRT to reduce 1 spray/nostril q1–5 hr
• Max:10 sprays/hr or 80 craving and withdrawal
Inhaler •  4 mg/cartridge Short-term NRT to reduce 1 cartridge inhaled over 20
• Max: 16 cartridges/d craving and withdrawal min q1.5–6 hr
Bupropion (Zyban) 150 mg Block nicotinic receptors 1 tablet daily × 3 d, then 1
and reduces reward tablet twice daily for 7–12
Varenicline (Chantix) 0.5 or 1 mg Dopaminergic reward and 0.5 mg daily × 3 d, then
partial nicotinic receptor 0.5 mg twice daily × 3 d,
antagonist then 1 mg twice daily
Adult Smoking Habits in Great Britain, 2013

The proportion of the GB adult population who smoke cigarettes has
fallen by more than a half in the last 40 years, from 46% in 1974 to
19% in 2013. Not only have fewer people taken up smoking, but more
of those who did smoke have quit

Women accounted for the fall on the previous year - the proportion of
women who smoke cigarettes fell from 19% to 17% between 2012 and
2013. There was relatively little change in this proportion for men

Unmarried people were almost twice as likely to be cigarette smokers
as married people
The proportion who smoke cigarettes was higher amongst unemployed
people, people working in routine and manual occupations and those
with lower level educational qualifications. These are all factors
associated with poverty

E-cigarettes are almost exclusively used by smokers and ex-
smokers. Almost none of those who had never smoked
cigarettes were e-cigarette users
Use of e-cigarettes, and the relationship to smoking

The debate around use of e-cigarettes:

E-cigarettes have been sold since 2004, and in Europe since 2006. Their
popularity and availability has increased, which has led to debate around their
use. Some feel that e-cigarettes could renormalise smoking, or 
could be a gateway to smoking by introducing non-smokers to nicotine. Others
feel that they could be a useful tool in the effort to reduce tobacco consumption.
To date, e-cigarettes have mainly been 
marketed as a cheaper and healthier alternative to smoking. However, the long-
term health effects of using e-cigarettes have yet to be established. This has led
to a World Health Organisation call for tighter controls on e-cigarettes.

ONS has chosen to publish preliminary findings on e-cigarette use in response
to the emerging need for more information. These data were collected between
January and March 2014. Complete 2014 findings are planned for publication as
part of the next Adult Smoking Habits in GB publication in 2015.
E-cigarettes were almost exclusively used by smokers and ex-smokers, Fig

More than 1 in 10 (12%) of cigarette smokers also used e-cigarettes,
compared with 1 in 20 (5%) ex-smokers and almost none of those who had
never smoked.

These findings reflect those from a YouGov survey commissioned by Action
on Smoking and Health (ASH). Data on e-cigarette use have also been
collected as part of the Smoking Toolkit Study.

E-cigarettes were found to be used mainly as smoking cessation aids and for
the perceived health benefits (compared with smoking tobacco). Over half
of e-cigarette users said that their main reason for using e-cigarettes was to
stop smoking, and about one in five said the main reason for their use was
because they thought they were less harmful than cigarettes.
Vaping advocates rightly suspect that these
nonprofits have exhibited “mission creep” as
they abandoned their public health goals by
lobbying to ban vaping and vapor products,
which protects deadly cigarettes and smoking
cessation drugs (whose manufacturers funded
the health groups) from future market
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
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

•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 patient’s and family’s perception of surgical risk and anticipated
Selective Estrogen Receptor Modulators - Concepts

•SERMs function as estrogen receptor (ER) agonists and
antagonists depending on the SERM structure and target
tissue. Predominant ERα receptors occur in the human
uterus, cortical bone, and the liver; whereas predominant
ERβ receptors occur in blood vessels, cancellous bone,
the whole brain, and immune cells.

•During carcinogenesis, the amount of ERα increases
while the amount of ERβ 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
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
risk-reducing agent intervention are not available to date.

• In the National Surgical Adjuvant Breast and Bowel
Project, tamoxifen-treated women with aBRCA2 mutation
but not a BRCA1 mutation 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 can be divided conceptually into four steps: tumor
initiation, tumor promotion, malignant conversion, and tumor

• DNA-adduct formation that causes either the activation of a proto-
oncogene 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 5α-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 5α-steroid reductase
inhibitor types 1 and 2 isoforms and has similar
anticarcinogenesis activity in preclinical models to

•Finasteride and dutasteride reduce the incidence of
Signal Transduction Modifiers - 1

•Difluoromethylornithine (DFMO) is an enzyme-
activated irreversible inhibitor of ornithine decarboxylase
(which is transactivated by the c-MYC oncogene and
cooperates with the RAS oncogene in malignant

•Topical-DFMO caused regression of cervical intraepithelial

•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

•No natural products have been studied in large
prospective, cancer incidence risk–reduction trials. 

•Statins and Bisphosphonates are still being studied.

•Multi-agent approaches are being conceptualized.