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Fundamentals
of Cancer Prevention
David S. Alberts
Lisa M. Hess
Editors
Fourth Edition
123
Fundamentals of Cancer Prevention
David S. Alberts • Lisa M. Hess
Editors
Fundamentals of Cancer
Prevention
Fourth edition
Editors
David S. Alberts Lisa M. Hess
University of Arizona Cancer Center Department of Obstetrics and Gynecology
Tucson, AZ Indiana University Schools of Medicine and
USA Public Health
Indianapolis, IN
USA
ISBN 978-3-030-15934-4 ISBN 978-3-030-15935-1 (eBook)

https://doi.org/10.1007/978-3-030-15935-1
© Springer Nature Switzerland AG 2019

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The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
David S. Alberts, MD
In my 44th year as a faculty member at the
University of Arizona Cancer Center, I want
to thank my research colleagues and the
administration for giving me so many
outstanding opportunities to express my
adventuresome academic spirit for so many
years. The University of Arizona Cancer
Center has been an exciting and
inspirational place to work!
First and foremost, I would like to pay tribute

to Lisa Hess, Ph.D., who is a brilliant cancer
prevention researcher with a wide breadth of
detailed knowledge in cancer
chemoprevention, healthcare outcomes, and
clinical trial design and management. I have
benefitted greatly from her wisdom, vision,
and outstanding editing capability over the
past 25 years.
I also want to thank all of the “Friends of the

Cancer Center,” who have made seminal
donations and continuous personal efforts to
our life-saving and health-promoting
laboratory-based cancer prevention research
programs. These kind and giving individuals
are too many to name, but a few that stand
out include family and friends: Bruce and
Betty Alberts, Tim Alberts, Ron and Emily
Axelrod, Tim and Diane Bowden, Barbie and
Michael Koff, Kaja LeWinn, and Sabrina
Plattner.
University of Arizona Cancer Center

wonderful donors/supporters: Barry, Paul
and Alice Baker, Nancy and Craig Berge,
Barbie Boyle, Jody Brase, Rose Marie
Bravo, Bill Budinger, Don Budinger, Dan
Cavanagh, Wally Chester, Ginny Clements,
Jim Click, Donald and Joan Diamond,
Bonnie Sedlmayr Emerson, Peter and Paula
Fasseas, Wayne and Amy Gould, Tom and
Ruthann Hornaday, Beth and Tony
Komadina, Leonard Lauder, Alan Levin, Alan
and Jan Levine, Helaine Diamond Levy,
Humberto and Czarina Lopez, Richard
Mallery, Pete Mendelson, Lute and Kelly
Olson, Mary Peachin, Donald Pitt, Laurel
Pracht, Colleen Ragland, Tom Rogers, Allan
Rudnick, Robert Sarver, Russ Skelton, Greg
Stanton, Chandler Warden, Jack Wilson,
Charlie and Barbara Young, Mel and Enid
Zuckerman.
My collaborators and brilliant researcher

partners: Peter Bartels, Jennifer W. Bea, Ann
Bode, Chris Brooks, Tom Brown, Setsuko
Chambers, Sherry Chow, Mary Clouser,
Clara Curiel Lewandrowski, William Dalton,
Sally Dickinson, Bob Dorr, Zigang Dong,
Janine Einspahr, Dianna Gilmore, Anna
Giuliano, Rayna Goldman, Sharon Don
Hanneman, Robin Harris, Ken Hatch, Shawn
Haywood, Stephanie Kha, Mary Krutzsch,
Peter Lance, Scott Lippman, Lois Loescher,
Ana Maria Lopez, Melody Maarouf, James
Marshall, Maria Elena Martinez, Frank
Meyskens, Maria Lluria Prevatt, Emanuel
“Chip” Petricoin, Gus Rodriguez, Lisa
Quale, Syd Salmon, Denise Spartonos, Steve
Stratton, Cyndi Thomson, Patricia
Thompson, Daniel Von Hoff, Betsey Wagener,
Joan Walker, James Warneke, Michael
Yozwiak, and Helen Zhang.
And finally, Heather Alberts my “wonder

woman,” savior and lover for 55 years.
Thank you from my heart.
Lisa M. Hess, PhD

My thanks go to David S. Alberts, with whom
I have worked throughout my career in
cancer prevention and control research.
Since I first joined the Cancer Center as a
graduate student in the early 1990s, Dave
has been my mentor, colleague, and most
importantly, a genuine friend. Most notably,
it has been a joy and privilege to write and
edit Fundamentals of Cancer Prevention
together since its first edition in 2003
through this year’s fourth edition in 2020.
I continue to thank my daughter, Rachael,

who every day teaches me the value of health
and motivates me to dedicate my work to
improve cancer prevention and care.
Contents
1 Introduction to Cancer Prevention�� 1

David S. Alberts and Lisa M. Hess
2 Assessing the Impact of Cancer Prevention on Self-Reported
Health and Well-Being�� 17
Stephen Joel Coons and Mira J. Patel
3 Assessing the Economic Value of Cancer Prevention �� 31
Benjamin M. Craig
4 The Role of Diet, Physical Activity, and Body Composition
in Cancer Prevention �� 53
Cynthia A. Thomson and Jennifer W. Bea
5 Innate and Adaptive Immune Responses to Cancer �� 111
Matthew P. Rausch and Karen Taraszka Hastings
6 Hereditary Risk for Cancer�� 161
Kate Shane-Carson and Joanne M. Jeter
7 Cancer Health Disparities �� 199
B. Lee Green, Jenna L. Davis, Desiree Rivers, Kyrel L. Buchanan,
and Kosj Yamoah
8 Human Categories and Health: The Power of the Concept
of Ethnicity �� 247
Kathryn Coe
9 Cancer Alternative Medicine and Cancer Prevention Research �� 269
A. I. Chang, A. H. Schwertschkow, H. Greenlee, L. K. Larkey,
J. Bloom-Foster, and L. E. Mehl-Madrona
10 Telemedicine, Telehealth, and e-Health Technologies
in Cancer Prevention �� 333
Ana Maria Lopez
11 Global Cancer Prevention �� 353
Janet Okamoto and Scott J. Leischow
ix
x Contents
12 Sunscreen-Based Skin Protection Against Solar Insult: Molecular

Mechanisms and Opportunities�� 377
Andrea Krajisnik, Jessica Perer, and Georg T. Wondrak
13 Skin Cancer Prevention�� 405
Maria Lluria-Prevatt, Sally E. Dickinson, and David S. Alberts
14 Colorectal Cancer Prevention�� 473
Peter Lance
15 Lung Cancer Prevention �� 511
Eva Szabo
16 Breast Cancer Prevention�� 543
Patricia A. Thompson, Christina Preece, and Alison T. Stopeck
17 Prostate Cancer Prevention�� 607
Amit M. Algotar and Anne Cress
18 Cervical Cancer Prevention�� 629
Katherine LaVigne and Mario M. Leitao Jr
19 Endometrial Cancer Prevention �� 653
Paulina Cybulska and Mario M. Leitao Jr
20 Epithelial Ovarian Cancer Prevention�� 677
Setsuko K. Chambers and Lisa M. Hess
21 Cancer Survivorship�� 723
Allison Barrie, Steven Plaxe, Robert Krouse, and Noreen M. Aziz
Introduction to Cancer Prevention
1
David S. Alberts and Lisa M. Hess
Contents
1.1 Introduction 2
1.2 Overview of Cancer Prevention 3
1.3 Primary Prevention 5
1.4 Secondary Prevention 7
1.5 Tertiary Prevention 7
1.6 Molecular Approach to Carcinogenesis 8
1.7 Cancer Prevention Clinical Trials 10
References 14
The reduction in cancer observed in the United States (US) is primarily due to
advances in and improved access to cancer detection and prevention efforts, result-
ing in less exposure to risk factors such as tobacco (Jemal et al. 2010). As a result,
an estimated 767,100 cancer deaths have been averted over the past two decades
(Jemal et al. 2010). These averted deaths are largely driven by reductions in lung
cancer (reduction in tobacco use), breast cancer and colorectal cancer (due to
improved screening and treatment modalities), cervical cancer (Pap testing and the
HPV vaccine), as well as lymphoma, leukemia, and testicular cancer (due to new
treatments). Unfortunately, these efforts to reduce the burden of cancer have not
been distributed equitably around the world. For example, the incidence of cervical
cancer is increasing in some areas (e.g., Zimbabwe, Uganda, Eastern Europe),
D. S. Alberts (*)
College of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA
e-mail: dalberts@azcc.arizona.edu
L. M. Hess
Department of Obstetrics and Gynecology, Schools of Medicine and Public Health, Indiana
University, Indianapolis, IN, USA
e-mail: lmhess@iupui.edu
© Springer Nature Switzerland AG 2019 1

D. S. Alberts, L. M. Hess (eds.), Fundamentals of Cancer Prevention,
https://doi.org/10.1007/978-3-030-15935-1_1
2 D. S. Alberts and L. M. Hess
perhaps due to lack of access to vaccination, increasing HPV infection rates, and
gaps in screening programs (Torre et al. 2016).
Other cancers have increased in the US and Western Europe, such as liver cancer
in part due to increasing hepatitis C infection rates, while liver cancer has decreased
in China and Japan, where public health programs have decreased the rate of hepa-
titis C infection (Torre et al. 2016).
Despite the reduction in incidence and mortality rates, particularly in high-
income countries, cancer remains a significant public health burden. Cancer is the
second leading cause of mortality in the US, where cancer causes approximately
609,640 deaths per year and is responsible for 8.2 million deaths worldwide each
year (Siegel et al. 2018; Torre et al. 2016).
1.1 Introduction
The concept of cancer prevention has changed with a greater understanding of the
genetic and molecular basis of carcinogenesis. Certainly, it is understood that a
person with cancer is not well one day and the next day diagnosed with cancer. It is
estimated that there is an average lag of at least 20 years between the development
of the first cancer cell and the onset of end-stage metastatic disease for a broad range
of solid tumors. In that there are an estimated 14.1 million new cancer cases diag-
nosed worldwide each year (Torre et al. 2016) and given the 20+-year lag time, it is
estimated that up to 280 million “healthy” adults currently harbor ultimately deadly
cancers, many of which may be fully preventable. Beyond reducing cancer inci-
dence, it is also estimated that between one-third and one-half of all cancer deaths
could be avoided with a combination of primary prevention, early detection, and
access to effective treatment; with our current knowledge, approximately three mil-
lion cancer deaths could be avoided each year through cancer prevention and con-
trol programs (Stewart and Wild 2014).
Cancer prevention strategies may represent effective and cost-effective opportu-
nities to dramatically reduce cancer mortality in the next decades. The World Health
Organization (WHO) estimates that the cost of cancer will reach US$458 billion per
year by 2030 and that implementing a basic package of cancer prevention initiatives
to address tobacco use, alcohol consumption, dietary behaviors, and physical inac-
tivity would only cost US$2 billion per year (Stewart and Wild 2014). However, it
is important to consider that in addition to these healthcare costs, there are consider-
able human costs of cancer that cannot be quantified in economic units. The physi-
cal suffering and psychosocial burden associated with cancer diagnosis, treatment,
and end-of-life care are inestimable. Globally, it is expected that there will be 22
million new cases of cancer diagnosed annually by 2030, with the greatest risk
among low- and middle-income nations. It is crucial to ensure that public health and
national priorities focus on cancer prevention efforts that address inequalities in
healthcare access and delivery (Bray et al. 2015).
1 Introduction to Cancer Prevention 3
1.2 Overview of Cancer Prevention
Cancer is a global term for a variety of diseases that share some similar characteris-
tics, such as uncontrolled cellular growth, enhanced angiogenesis, tissue invasion
and metastases, genomic instability, and/or reduced programmed cell death
(Hanahan and Weinberg 2000). The site of origin of the disease is used to define
general categories of disease (e.g., breast cancer, skin cancer); however, the site of
disease alone masks the significant heterogeneity of histological and pathological
subtypes within cancers. Cancer prevention research works to identify molecular
and cellular changes and to develop interventions as early as possible to reduce the
risk of their progression to cancer. Inherent to the challenges of prevention research
is the biologic complexity in the multitude of potential cancer-causing mutations
even within a single tumor. For example, over 33,300 and 22,900 somatic mutations
have been identified in melanoma and non-small cell lung cancer, respectively
(Stewart and Wild 2014).
It is estimated that there are over 14.1 million cases of cancer diagnosed and 8.2
million deaths each year worldwide (Torre et al. 2016). The five most common
worldwide cancers among men, excluding nonmelanoma skin cancer, include lung,
prostate, colorectal, stomach, and liver cancer, whereas for women the most com-
mon cancers are breast, colorectal, lung, cervix, and stomach (Table 1.1). It is esti-
mated that 80% of the burden of cancer is found in low- and middle-income
countries (Bray et al. 2012). As population and economic changes occur, infection-
related cancers (e.g., cervical, stomach) are decreasing whereas cancers associated
Table 1.1 Worldwide annual cancer incidence and mortality of selected common cancers (Stewart
and Wild 2014)
Number of new cases each year Number of deaths each year
Males
All cancers 7,427,148 4,653,132
Lung 1,241,601 1,098,606
Prostate 1,111,689 307,471
Colorectum 746,298 373,631
Stomach 631,293 468,931
Liver 554,369 521,031
Bladder 330,360 123,043
Esophagus 323,008 281,212
Females
All cancers 6,663,001 3,547,898
Breast 1,676,633 521,817
Colorectum 614,304 320,250
Lung 583,100 491,194
Cervix 527,624 265,653
Stomach 320,301 254,096
Uterine 319,905 217,680
Ovary 225,500 140,200
with modifiable behaviors such as dietary factors are increasing (e.g., breast, pros-
tate, and colorectal cancers) (Bray et al. 2012). Not only do cancer sites vary by
region due to differences in exposure to infection and varying activity and dietary
patterns, but the type of cancers as well. Esophageal cancers occur most commonly
in Malawi, South Africa, and Iran. In these high-risk areas, squamous cell carci-
noma is most common, possibly due to nutritional status and dietary patterns,
whereas in Western countries, adenocarcinomas are more common. The risk factors
associated with esophageal adenocarcinoma include smoking and gastrointestinal
reflux disease, which are more common in overweight or obese adults (Bray et al.
2012). Therefore, not only are the patterns of cancer incidence and mortality associ-
ated with regional variation, but the histological subtype as well.
As the world increasingly adopts behaviors that are associated with risk factors
of Western countries (e.g., increased body weight, reduced physical activity), the
rates of breast and colorectal cancers are increasing in parallel. Globally, obesity
rates doubled from 1980 to 2008 and continue to increase (Stevens et al. 2012). As
this trend continues, global cancer incidence rates will also continue to rise.
Contributing to the challenges faced by cancer prevention and early detection
efforts is the lack of access to health care due to either a lack of health insurance
(e.g., US) or a lack of healthcare services (rural or remote regions and many devel-
oping nations). Access to screening programs and improved healthcare programs
are essential to prevent cancer or to detect a cancer while it may still be curable. For
example, breast cancer rates have been increasing worldwide; however, the mortal-
ity due to breast cancer has been decreasing in higher income nations, such as the
US, Denmark, and Australia, likely due to improved screening/early detection and
access to more effective cancer treatment agents (Stewart and Wild 2014). Similarly,
among nations with organized cervical cancer screening programs, the risk of cervi-
cal cancer morbidity and mortality has been continuously declining (e.g., Sweden,
Finland, and France have all seen cervical cancer decrease by greater than 4% per
year since the initiation of cervical cancer screening programs). However, among
nations that lack these programs, cervical cancer remains a major health risk for all
women (e.g., Slovakia and Slovenia have seen annual increases in cervical cancer
without these programs) (Mackay et al. 2006). Currently, more than 70% of the
burden of cervical cancer occurs in low- to middle-income nations, and is the lead-
ing cause of death in more than 40 countries (primarily in Africa and South America)
(Stewart and Wild 2014).
Countries that have organized tobacco control policies have shown decreases in
youth tobacco use. While a World Health Organization survey reports that 92%
of the 176 countries reported to have tobacco control programs in place, only 69%
also have a funded/operational tobacco policy (Stewart and Wild 2014). Even
among nations that have established public health policies, individuals must have
access to these programs for them to be effective. The US has the highest per capita
healthcare expenditures in the world at approximately US$9237 per person per year
in 2015 (Dieleman et al. 2017), which is expected to reach nearly US$16,000 per
person by 2025 (Keehan et al. 2017). There is a great deal of variability worldwide.
High-income nations spend an average of US$5221 per person (range: 853–9237),
upper middle-income nations spend $914 per person (range: 228–1980), lower mid-
dle-income nations expend an average of $267 (range: 92–791), and low-income
nations spend $120 per capita (range: 33–347) (Dieleman et al. 2017). Despite the
investment in healthcare costs in the US, approximately 14.6% of the population
does not have health insurance (National Center for Health Statistics 2017). This is
an improvement from the nearly 20% of the population that did not have insurance
only 5 years earlier. Healthcare policies, such as the Affordable Care Act, have had
an impact on access to health insurance in several groups, particularly among young
adults. Due to the provision to require insurers to cover children through the age of
26, gaps in insurance coverage have been reduced from 34% in 2010 to 16% in 2015
(National Center for Health Statistics 2017). Certainly more work must be done to
ensure that no individual in any country lacks access to affordable health care. Lack
of access to health care has been demonstrated to result in late cancer diagnosis
(e.g., at an advanced stage) when costs are greater and outcomes are poor, more
cancer treatment delays, and ultimately higher mortality (ACS 2008). Even when
patients without insurance are diagnosed at the same stage as patients with insur-
ance, they still have a significantly increased risk of death (e.g., patients without
insurance have a 30–50% higher rate of death from colorectal or breast cancer than
patients with insurance) (IOM 2002).
The goal of cancer prevention is to reduce the morbidity and mortality from can-
cer by reducing the incidence of cancer due to these modifiable factors as well as to
reduce the impact of unmodifiable factors contributing to cancer. The development
of effective cancer prevention strategies has the potential to impact a significant por-
tion of the cancer-related deaths each year worldwide (Jemal et al. 2011). Therefore,
cancer prevention is the best approach possible to reduce the burden of cancer
worldwide. Cancer prevention research takes a three-pronged approach to target
different aspects reducing cancer morbidity and mortality: primary, secondary, and
tertiary prevention.
1.3 Primary Prevention
The goal of primary prevention is to prevent a cancer from beginning to develop.

Primary prevention involves a reduction of the impact of carcinogens on changes
that occur at the cellular level, such as through administration of a chemopreventive
agent or the removal of environmental carcinogens, or through changes in the tumor
microenvironment that can be influenced by lifestyle modification (e.g., reduction
in obesity to influence hormonal exposure). Primary prevention methods are best
suited for those cancers in which the causes are known. There are many factors
known to reduce overall cancer incidence, such as minimizing exposure to carcino-
gens (e.g., avoiding tobacco), dietary modification, reducing body weight, increas-
ing physical activity, avoiding infection, or through medical intervention (surgery
and/or chemoprevention). Among high-income nations, the leading risk factors for
cancer include an unhealthy diet, obesity, and tobacco use (together accounting for
40% of cases), whereas among developing nations poor diet/nutrition is the leading
risk factor in 20% of all cancer cases, and infection accounts for another 26% of all
cancer cases.
Tobacco use, which represents the greatest preventable cause of cancer death, is
the direct cause of more than 20% of all cancer deaths worldwide each year (primar-
ily lung cancer, but smoking also increases the risk of cancers of the larynx, oral
cavity, lip, nasal cavity, esophagus, bladder, kidney, cervix, stomach, liver, and
many other sites) (Thun et al. 2010). Tobacco use is the leading cause of smoking-
related cancer death among both men and women (80% of all lung cancers among
males and 50% among females are directly attributed to tobacco) (Jemal et al.
2011). However, all damage done during smoking is not completely irreversible.
Smoking cessation can begin to reverse the risk of cancer. Benefits from quitting
smoking begin within the first year of cessation and continue to increase over time.
The risk of lung, oral, and laryngeal cancers can be significantly reduced following
smoking cessation, with an estimated overall 9-year gain in life expectancy associ-
ated with smoking cessation (Jha et al. 2013). The results of tobacco cessation are
particularly pronounced if a person quits smoking before the age of 40 (associated
with a 90% reduction in premature death that is associated with smoking in midlife)
(Jha et al. 2013). Primary tobacco prevention efforts include cessation support pro-
grams (behavioral and pharmacologic), public awareness and education, smoke-
free public policies, increased tobacco pricing through taxation, and very importantly
efforts to reduce the initiation of the use of any form of burnt and smokeless tobacco,
all of which are carcinogenic and deadly (Thun et al. 2010; Jemal et al. 2011).
Many cancers are directly attributable to viral or bacterial infections (e.g., human
papillomavirus, HPV, infection is a necessary factor in the development of cervical
cancer; Helicobacter pylori is an initiator and promoter for gastric cancer). Advances
in vaccination research led to the development of HPV vaccines that are available to
young adults. If these vaccines would be used and available worldwide, nearly all
cervical cancers could be prevented. In the US, where the vaccine is widely avail-
able but no public health policy exists, approximately 50% of all young women and
38% of young men are vaccinated (Walker et al. 2017). As a result, half of the US
population remains at risk for cervical cancer. The adoption of HPV vaccination is
highly variable worldwide. In the UK, where a national coverage for HPV vaccina-
tion exists, nearly 90% of all young adults have received all courses of the HPV
vaccine (Sipp et al. 2018). In Japan the public health recommendation for vaccina-
tion was withdrawn, leading to a drop in vaccination rates from 70% to less than 1%
(Sipp et al. 2018). The role of public health policy and national coverage policies to
ensuring the health of nations cannot be understated.
Despite this known need primary prevention research and efforts continue to
remain underfunded. The National Institutes of Health, the government-funded
health research organization in the US, dedicated US$5894 million (approximately
18% of the program budget) to cancer research in 2017 (HHS 2016). Of this can-
cer-specific budget, only 5.5% is dedicated to cancer prevention and control (NCI
2018). This lack of prioritization results in delays in improving and delivering
early detection and prevention strategies that have the potential to save millions of
lives.
1.4 Secondary Prevention
Secondary prevention refers to screening efforts for early detection and diagnosis. The
goal of secondary prevention efforts is to identify abnormal cells or lesions before they
develop into a malignant tumor. Secondary prevention efforts are most effective where
there is a known precursor lesion to cancer (e.g., mammogram to identify and remove
ductal carcinoma in situ, colonoscopy to remove adenomas). By identifying abnormal
changes before they become cancerous, the precancer can be removed before it
becomes malignant. In some cases, secondary prevention can involve the treatment of
precancerous lesions in an attempt to reverse carcinogenesis (e.g., such as topical thera-
pies for nonmelanoma skin cancers, which cause the lesion to regress). Secondary pre-
vention is described in more detail specific to each disease site in this book. Secondary
prevention efforts are not possible for all cancers until accurate and effective screening
strategies are developed. Ovarian cancer, for example, has no known precursor lesion
and no testing strategy has been found to be effective to apply to a broad population.
Efforts have been underway by many organizations (e.g., Gynecologic Oncology
Group/NRG, UK Collaboration) to identify a strategy using existing approaches such
as transvaginal ultrasound and serum CA-125. The high rate of false-positive and false-
negative results, invasiveness of testing, and lack of cost-effectiveness even among the
highest risk populations have precluded any national screening efforts for ovarian can-
cer (Menon et al. 2017; Skates et al. 2017). Other diseases, such as stomach cancer,
are relatively rare in Western countries, limiting the value of screening programs in
those regions. However, Asia has higher incidence rates of stomach cancer (e.g., Japan,
Korea, and China account for 60% of the world’s stomach cancer cases). The imple-
mentation of population-based screening programs has led to earlier stage diagnosis
and improved survival outcomes (Balakrishnan et al. 2017). Five-year survival from
stomach cancer is nearing 70% in Japan and Korea whereas the 5-year survival is only
31% in the US (Balakrishnan et al. 2017; Noone et al. 2018).
1.5 Tertiary Prevention
Tertiary prevention involves the care of established disease and the prevention of
disease recurrence as well as the prevention of disease-related complications.
Tertiary prevention efforts also encompass the care of patients at high risk of devel-
oping a second primary cancer. Tertiary prevention may involve a variety of aspects
of survivorship, such as quality of life, maintenance therapies, surgical intervention,
palliative care, or diet and physical activity. Emerging evidence suggests that physi-
cal activity may have a greater impact on reducing cancer risk than nutritional inter-
ventions to reduce the risk of disease recurrence and to prolong survival in
early-stage breast cancer. In a prospective study of women with early-stage breast
cancer (George et al. 2011), women with any physical activity and better quality
diets had a lower risk of death from breast cancer than those who had poor nutrition
and exercise; nutrition alone did not demonstrate any differences between groups
(Fig. 1.1). These findings are hypothesis generating rather than confirmatory due to
10.00 %
No exercise
9.00 % 8.10 % 8.20 %
8.00 % Any exercise
7.00 %
6.20 %
6.00 %
5.00 %
4.00 %
3.00 %
2.00 % 1.60 %
1.00 %
n = 37 n = 130 n = 73 n = 430
0.00 %
Women with poor nutrition Women with better nutrition
Fig. 1.1 Percentage of deaths due to breast cancer in patients with early-stage disease according
to the amount of exercise and nutrition after diagnosis (George et al. 2011)
the self-reported diet and activities and non-randomized study design. Additional
research is ongoing to explore this hypothesis in breast cancer and a variety of other
tumor types, such as ovarian cancer in GOG-225 (the LIVES Study) (Thomson
et al. 2016). In the LIVES Study (Lifestyle Intervention for Ovarian Cancer
Enhanced Survival), 1200 women who have completed primary treatment for stage
II–IV ovarian cancer are randomized to a plant-based, high-fiber, low-fat diet (simi-
lar to that used in the Women’s Health Initiative that was associated with the 40%
reduction in the risk of ovarian cancer) plus physical activity or to usual care. This
study is nearing completion of enrollment in 2018, and will be the largest lifestyle-
based intervention in a randomized trial of ovarian cancer survivors to date.
1.6 Molecular Approach to Carcinogenesis
Cancer prevention research has been evolving from an initial understanding of the
process of cancer initiation and the steps to progression of disease. Carcinogenesis
refers to the process of genetic alterations that cause a normal cell to become
malignant and can take many years to develop (Fig. 1.2). For example, in the case
of colorectal cancer, it may take up to 35 years from the first initiated colonic
mucosal cell to an adenomatous polyp to develop invasive cancer. The same is
true for prostate cancer, which progresses over as many as 40–50 years from mild
to moderate, then severe intraepithelial neoplasia, to latent or invasive cancer.
Carcinoma
Normal Initiated Mild Moderate Severe in situ Cancer
Precancer = IEN
Colon Adenoma
5–20 years 5–15 years
Breast Atypical hyperplasia DCIS

14–18 years 6–10 years
Fig. 1.2 Progression of precancer to cancer in humans is a multiyear process (adapted from
O’Shaughnessy et al. 2002)
The process of carcinogenesis involves multiple molecular events over many

years to evolve to the earliest dysplastic lesion. This multiyear process provides
numerous opportunities to intervene with screening, early detection, surgical pro-
cedures, and chemoprevention (i.e., the use of specific nutrients and/or chemicals
to treat precancerous lesions and/or delay their development) (Sporn 1976). The
understanding of molecular pathways in carcinogenesis has grown rapidly in recent
years, fostering novel targeted approaches to cancer prevention research. The hall-
marks of cancer (e.g., cellular proliferation, lack of growth suppression, cellular
immortality and resistance of cellular death, cellular replication, inflammation,
angiogenesis, invasion, and metastasis) can further target prevention efforts to
intervene at multiple steps in the path of carcinogenesis (Gupta et al. 2018; Hanahan
et al. 2011).
Advances in the field of immunotherapy for cancer may provide valuable
insights into further targets for chemoprevention by targeting pathways of
immune response to block carcinogenesis. Premalignant cells are found in an
inflammatory state that has been found to promote cellular growth and prolifera-
tion (Hanahan et al. 2011). The cellular microenvironment can be prevented from
becoming immunosuppressive through vaccination for hepatitis B and C (hepa-
tocellular carcinoma) or for HPV (cervical carcinoma). However, cancer usually
begins with a precancerous lesion, not always an infection, and the challenge
remains to ensure detection at an early enough stage for a vaccine to be effective
(Morrison et al. 2018). While the development of primary prevention vaccines is
a promising strategy, additional work is needed to identify appropriate biomark-
ers and to ensure that sufficient patient populations are available for prevention
clinical trials.
1.7 Cancer Prevention Clinical Trials
The importance of conducting and participating in clinical trials cannot be under-

stated. Every person is at risk of genetic mutations that may lead to cancer. Due to
endogenous or exogenous factors, every human body has undergone genetic altera-
tions. For many individuals, these initiating factors are the early steps in the devel-
opment of cancer. The time period from the first initiated cell to malignancy is
estimated to be approximately 20 years for several cancers that are associated with
lifestyle and behavioral choices (e.g., tobacco, obesity, diet). As described earlier,
the early steps towards cancer occur over time, which means that millions of indi-
viduals worldwide are currently in some phase of undetected cancer progression
that will ultimately result in their death without early detection and prevention
(Wattenberg 1993). However, there is a need for improved strategies to effectively
prevent these untimely cancer deaths.
Cancer prevention trials are research studies designed to evaluate the safety and
effectiveness of new methods of cancer prevention or screening. The focus of cancer
prevention research can involve chemoprevention (including vaccination), screen-
ing, genetics, and/or lifestyle changes (e.g., diet, exercise, tobacco cessation).
Cancer chemoprevention research differs from treatment research in several impor-
tant ways as shown in Table 1.2. Cancer chemoprevention trials generally are per-
formed in relatively healthy volunteers who have well-documented precursor
lesions (e.g., colorectal adenomas, bladder papillomas, breast ductal carcinoma in
situ, actinic keratosis in the skin) or are at increased risk due to genetic or other fac-
tors. These trials are usually double blind (i.e., both physician and participant do not
know the assigned treatment) and placebo controlled and involve a few thousand to
tens of thousands of randomized participants. As opposed to cancer treatment phase
III trials that rarely extend beyond 5 years in duration, cancer chemoprevention tri-
als often take many years to complete and are extremely costly. The high cost of
cancer prevention trials and the need to develop reliable and meaningful intermedi-
ate endpoints are significant barriers that must be overcome. Cancer prevention
clinical trials take between 5 and 10 years (or more) to complete and require thou-
sands of participants. The cost to complete large-scale trials (10,000 participants or
more) can exceed US$100–200 million range and, of course, may not always result
in the discovery of an effective prevention strategy.
Research on developing and implementing effective cancer prevention and con-
trol interventions lags in funding relative to its potential impact on reducing the can-
cer burden. Despite the known cancer-causing effects of tobacco use, few non-nicotine
medications are currently approved by the US Food and Drug Administration (FDA)
for smoking cessation, though others are in the pipeline, and these existing medica-
tions achieve smoking cessation quit rates that are 25% at best. Since many health-
care organizations do not include smoking cessation medications as a covered
benefit, the incentive for pharmaceutical companies to prioritize the development of
smoking cessation medications is not high—thus fostering a negative feedback loop
that disincentivizes healthcare organizations from covering medications because the
effectiveness of those medications is low. Similarly, pharmaceutical companies have
Table 1.2 Cancer chemoprevention versus cancer treatment phase III trials
Characteristic Cancer chemoprevention trials Cancer treatment trials
Participants Relatively healthy volunteers with Patients diagnosed with
precancerous lesions or who are at moderate/ invasive cancer
high risk
Trial design Commonly double blind, placebo controlled Often unblinded to both
patient and investigator
Dosage Minimize dose, emphasize safety Maximize dose, emphasize
efficacy
Toxicity Toxicity is unacceptable, concern for Moderate toxicity acceptable
long-term use of agent due to severity of disease
Adherence Concern for “drop-ins” due to media or hype Concern for “dropouts” due to
toxicity
Endpoint Surrogate biomarkers; cancer incidence Mortality; disease progression
Sample size A few thousand to many thousands of A few hundred to a thousand
participants participants
Trial duration Usually 5–10+ years Several months to several
years
Revised from Alberts et al. (2004)
traditionally been unwilling to invest in the development of chemopreventive agents

because of the required length of time, size, and cost of registration trials. Furthermore,
companies are concerned about the unexpected, life-threatening toxicities that may
be observed with the long-term exposure required for many cancer prevention inter-
vention strategies. The majority of FDA-approved medications have been studied for
shorter treatment periods in trials of active disease, and the long-term safety profile
is unknown. Unexpected toxicity associated with long-term use of a drug can have an
extremely negative impact on approved products. This occurred with the investiga-
tion of selective cyclooxygenase-2 (COX-2) inhibitors for the prevention of colorec-
tal and prostate cancers. There are substantial preclinical data suggesting that the
COX-2/prostaglandin E2 (PGE2) pathway has a pivotal role in carcinogenesis
(Menter et al. 2010). COX overexpression was identified in several precursor lesions,
including cervical intraepithelial neoplasia, Barrett’s esophagus, colorectal adeno-
mas, actinic keratosis, and atypical adenomatous hyperplasia of the lung
(Subbaramaiah and Dannenberg 2003). Based on a growing body of evidence, inhi-
bition of COX-2, resulting in the inhibition of PGE2 production in the microenviron-
ment, was hypothesized to reduce the risk of a variety of cancers. A number of
chemoprevention clinical trials were initiated that randomized patients to COX-2
inhibitors, such as GOG-207 (14–18 weeks of celecoxib versus placebo for cervical
intraepithelial neoplasia, Clinicaltrials.gov: NCT00081263), the APPROVe trial
(156 weeks of rofecoxib versus placebo for adenomatous colorectal polyps,
Clinicaltrials.gov: NCT00282386), the ViP Trial (6 years of rofecoxib versus pla-
cebo among men with high PSA levels, Clinicaltrials.gov: NCT00060476), and cele-
coxib versus placebo (6 months of treatment for lung cancer incidence/recurrence in
heavy smokers, Clinicaltrials.gov: NCT00055978). In the midst of recruitment to
these chemoprevention trials, the APPROVe study identified a statistically significant
increased risk of cardiovascular events after 18 months of cumulative administration

of rofecoxib (Bresalier et al. 2005). This led not only to the early termination of many
studies evaluating COX-2 inhibitors, but also to the withdrawal of rofecoxib from the
market. This experience highlights the need for long-term safety data for chemopre-
vention trials that may involve treatment for longer durations of time. In addition to
lower tolerance for safety risk in prevention trials, there is a concern with unneces-
sary drug treatment of otherwise healthy adults, as not all adults at risk of cancer will
ultimately be diagnosed with the disease. The anticipated risk-benefit profile of any
chemopreventive agent must be thoroughly evaluated prior to initiating a cancer pre-
vention clinical trial, as minimizing risk is paramount.
The stages of investigation in cancer prevention research trials include a series of
phases of clinical trials. Phase I trials take place after an agent has demonstrated
activity with low toxicity in preclinical models. Phase I chemoprevention trials are
relatively brief (i.e., 1–3 months), preliminary research studies in healthy humans to
determine dose and safety of an agent. Phase II trials can be categorized into IIa
(non-randomized) and phase IIb (randomized) trials. Phase II studies are of longer
duration (i.e., 6–12 months), and typically include a surrogate efficacy endpoint,
such as a biomarker, to provide evidence regarding the effectiveness of the interven-
tion while continuing to evaluate safety. Phase III trials generally are large, double-
blind, multiple-year, placebo-controlled randomized trials to evaluate the efficacy
and safety of an agent in a sample of the target population. Often, cancer incidence
is the primary endpoint in phase III prevention studies. For a chemopreventive agent
to be used in a phase III research setting, it must meet several criteria. The agent
must have strong data supporting its mechanistic activity, and there must be pre-
clinical efficacy data from appropriate animal models. If the chemopreventive agent
is a nutrient, there must be strong epidemiologic data supporting its potential effec-
tiveness, and it must have demonstrated safety and activity in phase II trials. Phase
III trials of novel chemopreventive agents should not be performed in the absence of
a fundamental understanding of their mechanism of action. Phase IV trials are
focused on the utilization, effectiveness, and safety of an intervention in a real-
world setting. Inadequate funding and insufficient attention have been given for
these vitally important dissemination studies, leading to underutilization of effec-
tive chemoprevention strategies, such as tamoxifen or raloxifene to prevent the
development of breast cancer in postmenopausal women (Fisher et al. 1998). These
trials are typically single-arm long-term observational studies that evaluate a popu-
lation that receives the chemopreventive agent. Many phase IV studies are con-
ducted due to regulatory requirements to ensure that the risk/benefit profile remains
favorable in an uncontrolled setting after approval of the intervention (Biganzoli
and Cesana 2018). Pragmatic trials are a type of post-approval research; however it
combines aspects of both phase III designs (i.e., randomization) and phase IV fea-
tures (e.g., observational/uncontrolled). Pragmatic trials randomize a study partici-
pant to the chemoprevention agent versus control. In this case, the control may be
anything the patient and provider might normally consider, and is not mandated by
the trial. After randomization, the study is much like an observational trial, where
the intervention timing, outcome assessments, and other factors are not mandated
by the trial (Thorpe et al. 2009). This type of design basically provides balance on
baseline factors to conduct comparative effectiveness and safety research of a che-
moprevention agent.
Increasingly, health service research relies on administrative and clinical data-
bases (e.g., claims or electronic health records), to conduct retrospective observa-
tional research to evaluate real-world effectiveness of cancer prevention strategies.
These studies have the advantage of being less costly and of shorter duration than
prospective research. While these studies are also used to provide supporting evi-
dence for the development of cancer prevention interventions, the quality of real-
world data sources and the development of improved statistical methods to account
for heterogeneity and imbalance between cohorts have led to the increased use of
observational research to evaluate effectiveness after the completion of phase III
trials (e.g., propensity score methods, marginal structural models, use of an instru-
mental variable, sensitivity analyses) (Nørgaard et al. 2017; Streeter et al. 2017).
When the mechanism of action of a putative chemoprevention agent has not been
previously explored in the setting of broad, real-world populations, the results of
phase III trials can be alarming. Two examples of this include the results of the
Finnish Alpha-Tocopherol, Beta-Carotene (ATBC) Trial and the University of
Washington Carotene and Retinol Efficacy Trial (CARET). Both of these phase III
trials used relatively high doses of beta-carotene as compared to placebo in heavy
smokers to reduce the incidence of and mortality from lung cancer (Alberts et al.
1994; Omenn et al. 1996). Unfortunately, both trials found that the beta-carotene
intervention was associated with an 18–28% increase in lung cancer incidence and
an associated increase in mortality. Perhaps the reason for these unexpected and
extremely unfortunate results relates to the fact that at high beta-carotene concentra-
tions in the setting of high partial pressures of oxygen (e.g., as achieved in the lung)
and in the presence of heat (e.g., as achieved in the lung with cigarette smoking),
beta-carotene can become an autocatalytic prooxidant (versus its usual role as an
antioxidant) producing reactive oxygen species and DNA damage (Burton and
Ingold 1984).
The design of chemoprevention phase II–III trials must be founded on a hypoth-
esis that is soundly based on the mechanism of action of the agent, epidemiologic
data, safety profile, and its preclinical efficacy. The population to be enrolled to a
phase III prevention trial must be relatively at high risk, to assure that there will be
a sufficient number of events (e.g., precancers or cancers) to compare the treatment
to the control group. Phase III prevention trials should include both intermediate
(e.g., precancerous lesion regression or biomarker) and long-term (e.g., cancer inci-
dence) endpoint evaluations. Most importantly, the endpoint analyses should be
planned in advance, including well-defined and well-powered primary and second-
ary analyses.
One example of a high-impact phase III chemoprevention trial is the Breast
Cancer Prevention Trial with Tamoxifen (BCPT) (Fisher et al. 1998). Healthy
women at increased risk of breast cancer were randomized to either tamoxifen
(20 mg/day) or placebo for up to 5 years. Tamoxifen was selected for this trial
because of its well-documented mechanism of action (i.e., binding to the estrogen
receptor to prevent estrogen’s effect on tumor cell proliferation), its strong safety
profile in the setting of adjuvant breast cancer therapy, and its extreme activity in the
prevention of contralateral breast cancer in patients with stage I/II breast cancer.
After 69 months of follow-up, tamoxifen was found to be associated with an overall
49% reduction in the risk of invasive breast cancer (Fisher et al. 1998). The benefit
of breast cancer risk must be balanced with its toxicities, which include a greater
than twofold increase in early-stage endometrial cancer and an increased incidence
of deep vein thrombosis and pulmonary embolism. Since the publication of these
results, much discussion has led to the identification of women who would most
benefit from treatment with tamoxifen. Certainly, women who are at increased
breast cancer risk have already undergone a hysterectomy and who are at lower risk
for thrombophlebitis (e.g., due to higher levels of physical activity, lack of obesity)
would be good candidates for this intervention. Furthermore, there has been a rela-
tive lack of dissemination of this information to both primary care physicians and
the population, resulting in limited tamoxifen usage (Freedman et al. 2003). More
recently, the results of the phase III Study of Tamoxifen and Raloxifene (STAR)
revealed equivalent activity of tamoxifen as compared to raloxifene for the reduc-
tion of breast cancer risk among postmenopausal women at moderately increased
risk (Vogel et al. 2006). Raloxifene was associated with an improved safety profile
(e.g., lower thromboembolic events and cataracts), leading to its approval as a che-
mopreventive agent with the FDA. Only time will tell if these results will lead to
increased chemoprevention utilization. Currently, only a small fraction of eligible
women at increased risk of breast cancer are taking advantage of the established
efficacy of these chemopreventive strategies.
The translation of research findings to the clinic is the ultimate goal of cancer
prevention research. Chemoprevention agents or screening modalities must be
acceptable to the target population that would benefit from such interventions. For
example, the ideal chemoprevention agent would have a known mechanism of
action and would have no or minimal toxicity, have high efficacy, be available orally
or topically, have an acceptable treatment regimen, and be inexpensive. Similarly,
screening or early detection modalities should be minimally invasive, have high
sensitivity and specificity, and be acceptable to the target population. Interventions
that fail to maintain adequate adherence or that have high attrition rates during
phase III trials will likely also not be acceptable to the patient in clinical practice.
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Assessing the Impact of Cancer
Prevention on Self-Reported Health 2
and Well-Being
Stephen Joel Coons and Mira J. Patel
Contents
2.1 Introduction to Chapter 17
2.2 Outcome Assessment 18
2.3 Humanistic Outcomes 19
2.4 Measuring Humanistic Outcomes 21
2.5 Cancer-Specific Measures 21
2.6 Generic or General Measures 23
2.6.1 Health Profiles 23
2.6.2 Preference-Based Measures 23
2.6.3 Quality-Adjusted Life Years (QALYs) 24
2.7 Reviews of Empirical Evidence 25
2.8 Conclusion 26
References 27
2.1 Introduction to Chapter
Being able to do the things that bring meaning and fulfillment to our lives is a basic
human desire. However, cancer and its physical, emotional, and social consequences
can profoundly impair our ability to participate in those life-enriching pursuits.
Hence, to demonstrate the wisdom of individual, health system, and societal com-
mitment to cancer prevention activities, it is important to quantify, to the extent
S. J. Coons (*)
Patient-Reported Outcome Consortium, Critical Path Institute, Tucson, AZ, USA
e-mail: sjcoons@c-path.org
M. J. Patel
Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy,
Tucson, AZ, USA
e-mail: mpatel@pharmacy.arizona.edu
© Springer Nature Switzerland AG 2019 17

D. S. Alberts, L. M. Hess (eds.), Fundamentals of Cancer Prevention,
https://doi.org/10.1007/978-3-030-15935-1_2
18 S. J. Coons and M. J. Patel
possible, the short- and long-term impact of those activities on self-reported health
and well-being.
Cancer and its treatment can lead to significant burden on patients and their fami-
lies. It has been shown that cancer is the cause of more years of life lost than all
other causes of death (National Cancer Institute [NCI] 2017) and that being a cancer
survivor is associated with decreased physical health-related quality of life (Reeve
et al. 2009; Weaver et al. 2012), increased psychological distress (Hoffman et al.
2009), changes in cognitive functioning (Phillips et al. 2011), higher out-of-pocket
medical expenditures (Short et al. 2011), employment challenges (Short et al. 2005),
and greater risk for personal bankruptcy (Ramsey et al. 2011). Hence, the avoidance
of cancer and its consequences is paramount; where real change is possible in regard
to known modifiable behavioral, environmental, and policy/regulatory risk factors
for cancer, there is no doubt that “prevention is the cure” (Mukherjee 2010).
As will be described in much more detail in subsequent chapters, cancer preven-
tion takes many forms. At the individual level, virtually all prevention activities
involve (1) engaging in particular behaviors or interventions (e.g., following screen-
ing and immunization recommendations, taking tamoxifen for secondary preven-
tion of breast cancer), (2) avoiding particular behaviors (e.g., sunbathing, smoking),
or (3) changing particular behaviors once they have become habitual or routine
(e.g., quitting smoking, lowering dietary fat). Each of these prevention behaviors, or
the lack of them, can have short- and long-term impacts on health and well-being.
Therefore, it is important to discuss the value of cancer prevention activities and
the personal impact they can have on individuals who carry them out. The purpose
of this chapter is to provide an overview of the assessment of outcomes of cancer
prevention strategies in terms of self-reported health and well-being. However, it
must be recognized that most of the published literature in this field has focused on
individuals who already have a cancer diagnosis and are being treated. Hence, a
huge body of evidence exists regarding the impact of cancer and its treatment on
patient-reported functioning and well-being that provides a compelling case for pre-
venting cancer from occurring in the first place. On the other hand, much less
empirical evidence exists regarding the implications of cancer prevention activities
or interventions themselves on self-reported functioning and well-being.
2.2 Outcome Assessment
In order to discuss the impact of cancer and the substantial benefits of preventing it,
it is necessary to define outcomes. Death can be an outcome of cancer; however,
“death rates alone do not provide a complete picture of the burden that deaths impose
on the population” (NCI 2017). A more meaningful metric for measuring the impact
of death (and the value of preventing it) is person years of life lost (PYLL). PYLL are
the expected years of life lost due to premature death from a specific cause. Hence,
PYLL can help to illustrate the magnitude of cancer’s impact on shortening the
length of lives. In 2012, each person who died in the United States (US) as a result of
2 Assessing the Impact of Cancer Prevention on Self-Reported Health and Well-Being 19
cancer lost, on average, an estimated 15.7 years of life (NCI 2017). Overall, cancer-
related deaths in the US resulted in over 9.2 million PYLL in 2012, which suggests
that significant reductions in the number of life years lost to cancer can result from
prevention. It was projected that almost 610,000 people in the US will die of cancer
in 2018 (Siegel et al. 2018). Fortunately, death is not the only, nor most likely, out-
come of cancer. It was estimated that there were 15.5 million cancer survivors in the
US at the beginning of 2016 (American Cancer Society 2016) and the number is
projected to increase to almost 18 million by 2022 (Siegel et al. 2012).
A conceptual framework articulated by Kozma and colleagues places outcomes
into three categories: economic, clinical, and humanistic (Kozma et al. 1993).
Economic outcomes are changes in the consumption and production of resources
caused by disease or intervention, such as cancer prevention. The changes may be
direct (e.g., cost of a medication) or indirect (e.g., early retirement due to reduced
productivity). Clinical outcomes are the medical events that occur as a result of the
condition or its treatment as measured in the clinical setting. This includes death,
which will not be addressed further in this section. Humanistic, or patient-reported,
outcomes include condition or intervention-related symptoms and side effects,
treatment satisfaction, health status, and self-assessed function and well-being, or
health-related quality of life. It is important to recognize that progression-free sur-
vival, which is the most commonly used measure of treatment benefit in cancer
clinical trials, does not necessarily translate into quality-of-life improvements
(Brettschneider et al. 2011).
The major cancer clinical trial cooperative groups in North America and Europe
have recognized the importance of this outcome triad in evaluating and improving
the net benefit of cancer therapy (Bruner et al. 2004). Humanistic outcomes (e.g.,
self-reported health and well-being), which are the focus of this chapter, are increas-
ingly being incorporated into clinical trials (Lipscomb et al. 2004). In addition, the
importance of outcome assessment in cancer was reinforced with NCI’s establish-
ment of its Outcomes Research Branch in 1999 (Lipscomb and Snyder 2002) and
the Cancer Outcomes Measurement Working Group in 2001 (Lipscomb et al. 2005).
According to the NCI, “outcomes research describes, interprets, and predicts the
impact of various influences, especially (but not exclusively) interventions on ‘final’
endpoints that matter to decision makers: patients, providers, private payers, gov-
ernment agencies, accrediting organizations, or society at large” (Lipscomb and
Snyder 2002).
2.3 Humanistic Outcomes
As mentioned above, humanistic or patient-reported outcomes (PROs) include a

wide range of health-related concepts or constructs. According to the US Food and
Drug Administration (2009), a PRO is “any report of the status of a patient’s health
condition that comes directly from the patient, without interpretation of the patient’s
response by a clinician or anyone else.” PROs are on a continuum from the purely
20 S. J. Coons and M. J. Patel
symptomatic (e.g., pain intensity) to more complex aspects of functioning (e.g.,

ability to perform activities of daily living) to much more complex concepts (e.g.,
quality of life). Since many cancer prevention activities are aimed at populations
rather than individual patients, the term PRO in the context of this chapter may seem
too narrow; however, the intent is to convey the importance of capturing individual’s
health and healthcare perceptions and experiences through self-report. The PRO
that has increasingly garnered the most attention, particularly in regard to drug ther-
apy (Willke et al. 2004; European Medicines Agency 2005), is health-related qual-
ity of life or health-related functioning and well-being, which will be a primary
focus of this section.
Quality of life is a commonly used term that usually conveys a general feeling
rather than a specific state of mind. A person’s quality of life, or subjective well-
being, is based on personal experience and expectations that affect and can be influ-
enced by many factors, including standard of living, family life, friendships, and job
satisfaction (Sirgy et al. 2006). Although health can impact these factors, health care
is not directly aimed at enhancing them. Studies of health outcomes use the term
health-related quality of life to distinguish health effects from the effects of other
important personal and environmental factors. There is growing awareness that in
certain diseases, such as cancer, or at particular stages of disease, health-related
quality of life may be the most important health outcome to consider in assessing
the effect of interventions (Staquet et al. 1992).
In much of the empirical literature, explicit definitions of health-related quality
of life are rare; readers must deduce its implicit definition from the manner in
which its measurement is operationalized. However, some authors have provided
definitions. For example, Revicki and colleagues define health-related quality of
life as “the subjective assessment of the impact of a disease and treatment across
physical, psychological, social, and somatic domains of functioning and well-
being” (Revicki et al. 2000). Ferrans (2005) has provided a useful overview of
various definitions and conceptual models of health-related quality of life.
Definitions may differ in certain respects, but an important conceptual character-
istic they share is multidimensionality. Essential dimensions of health-related
quality of life include:
• Physical health and functioning

• Psychological health and functioning
• Social and role functioning
In addition, disease- and/or treatment-related symptomatology (e.g., pain), gen-

eral well-being, and spiritual well-being are sometimes assessed. The latter is more
likely to be included in measures developed for conditions that have the potential to
impact not only quality of life but length of life as well (e.g., cancer). For example,
the four-dimensional model that provides the framework for the cancer-related
quality of life questionnaires developed at the City of Hope National Medical Center
includes spiritual well-being along with physical, psychological, and social well-
being (Grant et al. 2004).
Another random document with
no related content on Scribd:
“I consecrate this interesting piece of furniture to American
Science, and to the Philosophical Society of Philadelphia: willing,
however, that in consideration of the high esteem I bear to you
personally, you should have the custody and use of it in your own
house, during your life; producing it only to the Society for the use of
the Secretary, when you think proper. I have subjoined by way of
postscript to this letter, some particulars relating to the Residence of
Copernicus, and his Tomb; which I wish you to communicate to our
Society.[287]
“Permit me to repeat my earnest request, that you should be kind

and attentive to the Bearer (and his Family,) who I hope will have the
happiness to obtain a literary establishment in the United States, and
prove of much utility to the public. I am, Sir, with esteem, your
obliged humble servant—
Buchan.”
“Dr. Rittenhouse, Pres. of the Am. Phil. Society.”
This really “interesting piece of furniture” was viewed by Dr.

Rittenhouse and the Philosophical Society, in the light it was
intended to be,—as a mark of the Donor’s good-will towards this
institution, and of his respect for the character of its President. The
Box has been disposed of, agreeably to his Lordship’s desire: it is
inserted in the list of Donations to the Society, prefixed to the fourth
volume of their Transactions, under the date of May 15, 1795, and it
is, at present, deposited in their Hall.
The friendship that subsisted between Dr. Rittenhouse and Mr.

Jefferson, was produced, in a great measure, by the congeniality of
these gentlemen in the concerns of science. The correct and
penetrating mind of the former knew how to estimate at their just
value, without over-rating them, the literary and scientific
acquirements of the latter; while, on the other hand, this last was
fully capable of discerning the sublime genius and most
extraordinary talents of that man whom he greatly admired. While
Mr. Jefferson resided in Philadelphia, as secretary of State, he made
frequent visits to Dr. Rittenhouse: he thus became intimately
acquainted with his character, for which he conceived the highest
respect; and, as a mark of his esteem for him, he presented him with
his own bust, in the costume of the day, cast in plaster, from one in
marble executed by Houdon, of Paris.
Mr. Jefferson has testified to the world the exalted opinion he

entertained of our Philosopher. In his refutation of the Count de
Buffon’s preposterous theory, “of the tendency of nature to belittle
her productions on this side the Atlantic,” he makes the following
remarks, on the assertion of another French philosopher[288]—that
America has not produced “one able mathematician, one man of
genius in a single art or a single science:”—“In war,” says Mr.
Jefferson, “we have produced a Washington, whose memory will
be adored while liberty shall have votaries, whose name will triumph
over time, and will in future ages assume its just station among the
most celebrated worthies of the world: when that wretched
philosophy shall be forgotten, which would have arranged him
among the degeneracies of nature. In physics,“ continues Mr.
Jefferson, “we have produced a Franklin, than whom no one of the
present age has made more important discoveries, nor has enriched
philosophy with more, or more ingenious solutions of the
phænomena of nature.—We have supposed Mr. Rittenhouse
second to no astronomer living: that in genius, he must be the first,
because he is self-taught. As an artist he has exhibited as great a
proof of mechanical genius, as the world has ever produced. He has
not indeed made a world; but he has by imitation approached nearer
its Maker, than any man who has lived from the creation to this
day.”[289]
Mr. Jefferson retained the highest esteem for Dr. Rittenhouse,

during his life; and it is believed this sentiment was mutual. Letters of
friendship were occasionally interchanged by them: part of one of the
latest of these, is as follows:
“Monticello, Feb. 24, 1795.
“Dear Sir,
....[290]
“I am here immersed in the concerns of a farmer, and more

interested and engrossed by them, than I had ever conceived it
possible. They in a great degree render me indifferent to my books,
so that I read little and ride much; and I regret greatly the time I have
suffered myself to waste from home. To this, indeed, is added
another kind of regret, for the loss of society with the worthy
characters with which I became acquainted, in the course of my
wanderings from home. If I had but Fortunatus’s wishing cap, to seat
myself sometimes by your fireside, and to pay a visit to Dr. Priestly, I
would be contented: his writings evince, that he must be a fund of
instruction, in conversation, and his character an object of
attachment and veneration.
“Be so good as to present my best respects to Mrs. Rittenhouse;

and to accept, yourself, assurances of the high esteem of, dear sir,
your sincere friend and humble servant,
“Th. Jefferson.
“David Rittenhouse.”
At this time, Dr. Rittenhouse still held the Directorship of the Mint,
though he resigned it a few months after; and from that period, his
health being then much on the decline, he seemed to be desirous of
passing the remainder of his days in tranquillity, and an abstraction
from all business and severe studies, in the society of his family and
a few particular friends. He now received numerous proofs of the
affectionate respect and high consideration, in which his person and
character were held; both among his own countrymen and in foreign
nations. Many of his fellow-citizens were assiduous in their attentions
to him: they frequently visited him; and, when he was suffering in his
health, he experienced repeated acts of friendship and kindness:—
President Washington often made calls upon him, and enquiries
concerning his health; and among his other friends, the late Mr.
Henry Hill and Mr. Robert Morris manifested towards him the kindest
attentions.
In the spring of the year 1795, our amiable Philosopher was
admitted a member of the Royal Society of London. He was apprized
of this new mark of distinction conferred on him, by the following
note, addressed to him by Phineas Bond, Esq. late the British
Consul, resident in Philadelphia.
“Chesnut Street, 15th June, 1795.
“Mr. Bond has the honour to inform Mr. Rittenhouse, that he has
received a letter from his friend Mr. George Chalmers, of the office of
the Lords of the Committee of Council for Trade, &c. at White-hall, in
which he requests him to apprize Mr. R. of his election as a Fellow of
the Royal Society of London, which took place on the 23d of April.
“Mr. B. begs leave to congratulate Mr. R. on this new honour, to

which his merits, as a Philosopher, so eminently entitle him.
“David Rittenhouse, Esq.”
It was not until towards the close of the summer, that Dr.
Rittenhouse received the certificate of his Fellowship, in the Royal
Society. His Diploma, for this honour, bears date the 16th of April,
1795;[291] and was accompanied by the following letter:
“Sir,
“Having the honour to transmit to you the Diploma of your election

into the Royal Society, as a foreign Member, I beg leave to
congratulate you on this proof of the high esteem in which you are
held by that illustrious body. I have the honour to be, with the
greatest respect, Sir, your most obedient and very humble servant.
“Charles Peter Layard.

“R. Society’s Apartments, Somerset Place,
“London, July 3d, 1795.”
The Royal Society of London has dealt out the honour of

Fellowship with a sparing hand, to foreigners; and very few
Americans have been admitted into that body, at any time: the Writer
does not recollect any others than Dr. Franklin, Dr. Johnson, formerly
of Connecticut, and the late Dr. Morgan and Mr. John Bartram, of
Philadelphia, who were Fellows of the Royal Society before the
American revolution; and since that period, he believes Dr.
Rittenhouse to have been one of but two or three native Americans
who have borne that mark of distinction.
Soon after Dr. Rittenhouse became associated with that illustrious

band of scientific men, a letter was written to him by Mr. Lalande, the
celebrated Astronomer of France; of which the following translation
is given in this place, as it will be perused with interest by the reader
versed in astronomy.
“Paris, at the College of France, May 14th, 1795.
“It is a long time, my dear Associate, since I have heard from you:
but Mr. Adet, our worthy ambassador, will probably procure for me
that satisfaction. You will see by the little history which I send you,
that the troubles of the revolution have not impaired my labours; and
that I have, now, twenty-seven thousand stars, observed.
“I have seen with great pleasure, in the transactions of your

Philosophical Society, the annular eclipse of 1791:[292] I have
calculated the conjunction 7h 42′ 19″; but I have been obliged to take
one minute from the phases of the ring, and to suppose {6h 49′ 30″} /
{6h 53′ 47″}, in order to agree, either with your end of the eclipse, or
the difference of meridians, already known with sufficient accuracy
by the transit of Venus, which gives 9h 10′ 6″; and your eclipse gives,
9h 10′ 3″, or 5h 0′ 43″ in relation to Greenwich.
“What has given me still greater pleasure, is, that the duration of
the ring, as you observed it, agrees very well with the diameters of
the Sun and of the Moon, which T have adopted in the third edition
of my Astronomy (1792), and the diminutions that I there propose for
eclipses; viz. 3″½ to be taken from the diameter of the Sun, and 2″
from that of the Moon.[293]
“I pray you to make many compliments for me, to the astronomers
whom I know, in your country, Mr. Willard at Beverley and Mr.
Williams at Cambridge: Is there any other astronomer, now, who
applies himself seriously to astronomy? I greet you with health and
brotherhood.
“Lalande.
“Professor of Astronomy, and Inspector of the
College of France,[294] Cambray Place.“
The mind of Dr. Rittenhouse, ever intent on doing, good, was

always zealously engaged on occasions which afforded him
opportunities of contributing to the rewards of merit and the
promotion of beneficial establishments, or useful undertakings of any
kind.
Such an occasion presented itself, at the close of the year 1795.

His nephew Dr. B. S. Barton, to whom he was attached by the
strongest ties of friendship, then held the Professorship of Botany
and Natural History in the University of Pennsylvania: but a vacancy
being at that time expected in the chair of the Materia Medica, which
branch of medicine was then taught by Dr. Samuel Powell Griffitts,
Dr. Rittenhouse exerted himself to obtain that appointment for his
nephew; upon whom it was conferred soon after, in conjunction with
the chair he already occupied.
With a view to the gratification of his anxious wishes, in the

attainment of this object, Dr. Rittenhouse addressed himself
personally to some of his colleagues in the board of trustees of the
University: and to Dr. M‘Kean, president of that board, he wrote the
following letter[295] on the subject.
“Philadelphia, Dec. 26th, 1795.
“Dear Sir,
“I am informed that Dr. Griffitts intends to resign his

Professorship in the University, sometime this winter. On this
occasion, I beg leave to recommend to your favourable notice my
nephew, Dr. Barton. He certainly has abilities sufficient to enable him
to be useful in any branch of medicine, and ambition enough to
induce him to make the greatest exertions: Besides, the Materia
Medica seems so nearly connected with Botany and Natural History,
his favourite studies, that I flatter myself he will be successful in his
intended application to the honourable Board of Trustees; yet I am
certain this will much depend on your interest. I am, Dear Sir, with
the sincerest affection and esteem, your most obedient Servant,
“David Rittenhouse.[296]
(Superscribed.)
“Hon. Thomas M‘Kean, LL. D.
Chief Justice of Pennsylvania.”
The affectionate regard and high respect which Professor Barton
uniformly cherished for the person and character of this worthy
relative,—who, on all occasions, evinced himself to be his sincere
friend,—cannot be better manifested, than by citing his own words.
In his dedication to Dr. Rittenhouse, of a dessertation, entitled, A
Memoir concerning the fascinating faculty which has been ascribed
to the Rattle-Snake and other American Serpents, is this passage
—“In inscribing this Memoir to you, dear sir, I follow the regular
course of my feelings, which, when I have received acts of friendship
or kindness, ever lead me to acknowledge them. Whilst your
example early implanted in me an ardent love of science, the
assistance which you afforded me, by removing many of the
obstacles that have opposed my advancement in life, has enabled
me to devote a portion of my time to the cultivation of science; and
thereby to increase the quantity of my happiness:” This was written
just four months before the decease of our Philosopher. And in a
subsequent inscription by the same gentleman,—that of his New
Views of the Origin of the Tribes and Nations of America,—dedicated
to Mr. Jefferson, and dated about a year after that event, he says:
“The only dedications I ever wrote, were to two persons[297] whom I
greatly esteemed and loved; the last, to a common friend, whose
virtues and science endeared him to his country, and whose removal
from us, we shall long have reason to deplore.”
Soon after Dr. Priestley’s arrival in Pennsylvania, our Philosopher

became personally acquainted with him, and presently conceived for
his fellow-labourer in science a sincere esteem. This was reciprocal;
and, therefore, while the celebrated English philosopher remained in
Philadelphia, and also when he occasionally visited that city after his
removal to the town of Northumberland on the Susquehanna, he
passed much of his time in Dr. Rittenhouse’s family. So far as the
pursuits of these gentlemen, in matters of science, were congenial—
for, in some respects they were very dissimilar,—their opinions
appeared to harmonize with each other: but, how far their sentiments
accorded on other subjects, or whether at all, the Writer cannot
undertake to pronounce; not possessing the necessary means to
enable him to do so with a sufficient degree of certainty. Dr.
Rittenhouse’s intercourse with Dr. Priestley, either personal or
epistolary, was, however, of short duration; being terminated by the
death of the former, in little more than two years after the latter first
came to Philadelphia. One of the last interviews which Dr.
Rittenhouse had with his friend Priestley, was very shortly before our
philosopher’s death: he was one of a select few whom the writer had
the pleasure of meeting at Dr. Rittenhouse’s, to dine, on the 18th of
March, 1796.
That learned and eminent foreigner,—for Dr. Priestley never
became a naturalized citizen of the United States,—died at
Northumberland in Pennsylvania, at an advanced age, on the 6th
day of February 1804.
The scanty remnant of life that yet remained to the great American
Astronomer and Mathematician, was neither uselessly, nor
altogether unpleasantly employed. In this interval of time, short as it
was, such portions of it as afforded him some respite from sickness
and pain, were either devoted to the society of his family and friends,
or occupied in study. From these sources of rational enjoyment, be
derived much comfort; and the solace he drew from them, was
greatly heightened by the endearing attentions, which, amidst the
rapid decline of his health and strength, he experienced, in an
eminent degree, in the bosom of his affectionate family and some
surrounding relatives. He was fully sensible of the approaching crisis
of his disease; and he appeared to be quite prepared to meet the
awful stroke, with the fortitude which a retrospective view of a well-
spent life would naturally inspire; as well as with the resignation,
which an entire confidence in the goodness, the wisdom, and the
mercy of his omnipotent Creator, taught him to be a duty. His
elevated conceptions of the Deity, together with his decided belief of
the immortality of the soul, according at the same time with the
doctrines of a pure religion, animated him with the stedfast hope of
an happy futurity, worthy of a Christian and a Philosopher. His
intimate knowledge of the sublimest works of creation, rendered him
highly sensible of the wisdom and power of the Great Supreme;
while that knowledge, aided by the lights furnished by the Christian
dispensation, led him to ascribe suitable attributes to the Author of
Nature,—a Being infinitely good, as well as perfect: for, as he once
familiarly expressed himself,[298] he was “firmly persuaded, that we
are not at the disposal of a Being, who has the least tincture of ill-
nature, or requires any in us.”[299]
It is an observation of a judicious biographer,[A] that “nothing can

awaken the attention, nothing affect the heart of man, more strongly,
than the behaviour of eminent personages in their last moments; in
that only scene of life where we are all sure, later or sooner, to
resemble them.” The writer of these Memoirs feels a sort of pensive
gratification, in having it in his power to announce the manner in
which the great American Astronomer deported himself, during the
closing scene of his life: The following information on this head, was
communicated by the writer’s brother, Professor Barton, the
deceased’s nephew and friend,—for some years, also, his family-
physician; and who, in his medical capacity, attended him in the
whole of his last illness.
“The last visit I ever received from Mr. Rittenhouse was about the
middle of June, 1796. He called at my humble habitation in Fifth
street, to inquire about my health, and to learn from me the result of
the experiments and inquiries in which he knew I was, at this time
engaged, concerning the mode of generation and gestation of our
opossum, an animal to whose economy and manners he had himself
paid some attention, and whose history he justly considered one of
the most interesting in the whole range of zoology.
“It was on this occasion, that our excellent friend first informed me,
that he had received a diploma from the Royal Society. He observed,
with a tone of voice and with a certain expression of countenance,
which were not calculated to afford me any pleasure, “that a few
years ago, such a mark of respect from that illustrious body would
have been received by him with pleasure and with pride.”
“In fact, Mr. Rittenhouse, now and for some months past, was
strongly impressed with the idea, that his career of usefulness and
virtue was nearly at an end. He had several times, during the
preceding part of the spring and summer, intimated to me (and
doubtless to others of his friends) his impressions on this head. In
what precise condition of his system, whether physical or intellectual,
these impressions were founded, I have only been able to form a
distant, and unsatisfactory conjecture.
“A few days after this interview, viz. on the 22d of June, I was sent
for to visit Mr. Rittenhouse. I found him in his garden, where he loved
to walk, and soon learned that he laboured under a severe attack of
cholera, accompanied, however, with more fever than we generally
find with this disease; and with a great increase of that violent pain
and sense of oppression at the region of his stomach, to which he
had been subject for at least thirty years. Notwithstanding his age,
the debility of his system, and the unfavourable state of the season, I
ventured to flatter myself, that the attack would not prove mortal. On
the following day, however, finding him no better, but rather worse, I
requested permission to call in the aid of another physician; and
having mentioned the name of Dr. Adam Kuhn, that gentleman
accordingly visited our friend, in company with me, during the
remainder of his illness.
His febrile symptoms being very urgent, it was thought necessary

to bleed our patient; and notwithstanding his great and habitual
repugnance to the practice on former occasions, he now readily
consented to the operation, on condition that I would perform it
myself. The blood which was drawn, exhibited a pretty strong
inflammatory crust; and the operation seemed to give him a
temporary relief from his pain. Soon after this, his strength gradually
declined; and on the third day of his illness, it was but too obvious,
that our illustrious relative was soon to be separated from his friends.
He expired without a struggle, and in the calmest manner, ten
minutes before two o’clock on the morning of Sunday the 26th, in the
presence of his youngest daughter, Mrs. Waters, and myself. His
excellent wife, who had ever been assiduous in her attention on her
husband, both in sickness and in health, had retired from his
chamber about two hours before, unable to support the awful scene
of expiring genius and virtue.
“There can be no doubt, I think, that Mr. Rittenhouse, from the first
invasion of his disease, or at least from the day when he was
confined to his bed or room, entertained but little hopes of his
recovery. He signed his will in my presence. He discovered no more
solicitude about his situation, than it is decorous and proper in every
good or great man to feel, when in a similar situation. During the
greater part of his illness, he manifested the most happy
temperament of mind: and it was only in the last hour or two of his
life, that his powerful intellects were disturbed by a mild delirium.
About eight hours before he died, the pain in the region of his
stomach being unusually severe, a poultice composed of meal and
laudanum was applied to the part. In less than two hours after the
application, I called to see him, and upon asking him if he did not feel
easier, he calmly answered, in these memorable words, which it is
impossible for me to forget,—for they were the last he ever distinctly
uttered, and they make us acquainted with the two most important
features in his religious creed,—“Yes, you have made the way to
God easier!”
“Such were the dying words, as it were, of our illustrious relative

and friend. He was dear to us both, to all his relatives and friends;
and to his country. To me, let me add, he was peculiarly dear. The
most happy and profitable hours of my life were passed in the
society of this virtuous man. I followed his foot-steps in the
wilderness of our country, where he was the first to carry the
telescope, and to mark the motions and positions of the planets. In
the bosom of his family, I listened to his lessons, as an humble
disciple of Socrates, or Plato. Science mixed with virtue was ever
inculcated from his lips.—But to me, Mr. Rittenhouse was more than
a friend and preceptor. He was a father and supporter. He laid the
foundation of what little prosperity in life I now, or may in future,
enjoy: and if it shall ever be my fortune, either by my labours or my
zeal, to advance the progress of science, or to reflect any honour
upon my country, I should be the most ungrateful of men, if I did not
acknowledge, and wish it to be known, that it was David
Rittenhouse who enabled me to be useful.”
Such was the death of David Rittenhouse,—soon after his

entrance into the sixty-fifth year of his age:—“Thus, with a heart
overflowing with love to his family, friends, country, and to the whole
world, he peacefully resigned his spirit into the hands of his God.”[300]
Thus did his immortal soul gently pass away, from this transitory but
variegated scene; from a theatre of mingled afflictions and comforts,
of privations and enjoyments, of absolute certainty with respect to
the non-continuance of this state, and of equal incertitude as to our
possible knowledge of the term of its duration:—And it is most
confidently believed, that his departed spirit, while yet hovering on
the confines of time, devoutly relied on being “promoted to a more
exalted rank among the creatures of God.”[301]
145. Joseph Galloway, Esq. a representative in assembly from the

county of Bucks. He was speaker of the house, from the year 1766
to 1773, inclusively; excepting a short interval in the session of 1768-
9, in which Joseph Fox, Esq. officiated as speaker.
146. William Allen, Esq. chief-justice of the supreme court of

Pennsylvania, and a member of assembly from the county of
Cumberland.
147. Equal to 533 Spanish or American dollars.
148. John and George Ross, Esqrs. lawyers of great

respectability, and brothers; the former a resident in Philadelphia; the
latter in Lancaster. Mr. George Ross was a member of the first
congress; and was appointed by the assembly on the 5th of April,
1775, judge of the admiralty-court for Pennsylvania.
149. Edward Biddle, Esq. a lawyer of eminence, and a

representative in assembly for the county of Berks, in which he
resided. This gentleman was one of the delegates appointed to the
congress of the 10th of May, 1775, under an unanimous resolution of
the assembly, passed in December, 1774; but, having succeeded Mr.
Galloway as speaker of that house, in the session of 1774-5, he did
not take his seat in congress, with his colleagues. These were John
Dickinson, Charles Humphreys, John Morton, George Ross, Thomas
Mifflin, Benjamin Franklin, Thomas Willing and James Wilson, Esqrs.
150. Emanuel Carpenter, Esq. long a respectable member of
assembly from Lancaster county.
151. Thomas Minshull, Esq. a respectable member of the house,

from York county.
152. The Hon. John Penn.—This worthy gentleman, a grandson of

the celebrated William Penn, was lieutenant-governor of
Pennsylvania, under the chief proprietaries of the province, from
October 1763, to May 1771; and again, from August 1773, until the
revolution.
153. The proprietary’s and governor’s council, consisting of James

Hamilton, William Allen, Joseph Turner, William Logan, Richard
Peters (D. D.), Lynford Lardner, Benjamin Chew, Thomas
Cadwallader, Richard Penn, James Tilghman, Andrew Allen, and
Edward Shippen, jun. Esquires. Joseph Shippen, jun. Esquire,
officiated many years as provincial secretary and clerk of the council.
154. Matthias Slough, Esq. who served several years with

reputation as a representative in the assembly, from the county of
Lancaster.
155. On the 4th of Feb. 1770, he mentioned to Mr. Barton his then
contemplated removal into that city, in these terms—“Dr. Smith, to
whom I am indebted for many kindnesses, is very urgent to have me
come to Philadelphia to reside, which it is probable I may do shortly:
but I am not yet determined. If I live to write again, you shall know
more of my mind; in the mean time, I shall be glad to have your
opinion of the matter.”
156. Since writing the above the author has ascertained, that
towards the close of April, 1770, the orrery was purchased for the
college of New-Jersey. On the 23d of that month, Dr. Witherspoon,
then the president of that college, accompanied by some gentlemen,
went to Norriton for that purpose, and it appears that the orrery was
then nearly finished.
157. The following extract of a letter from Dr. Smith to Mr. Barton,
written the day after Mr. Rittenhouse’s on the same subject, will
further explain the embarrassing circumstances that attended this
transaction, and the delicate situation in which Mr. Rittenhouse,
particularly, was placed.
“I never,” said the Doctor, “met with greater mortification, than to

find Mr. Rittenhouse had, in my absence, made a sort of agreement
to let his Orrery go to the Jersey College. I had constantly told him,
that if the Assembly did not take it, I would take it for our College,
and would have paid the full sum, should I have begged the money. I
thought I could depend, as much as on any thing under the sun, that
after Mr. Rittenhouse knew my intentions about it, he would not have
listened to any proposal for disposing of it, without advising me, and
giving our College the first opportunity to purchase. I think Mr.
Rittenhouse was never so little himself, as to suffer himself to be
taken off his guard on this occasion. This province is willing to
honour him, as her own: and believe me, many of his friends
wondered at the newspaper article; and regretted that he should
think so little of his noble invention, as to consent to let it go to a
village; unless he had first found, on trial, that his friends in this city
had not spirit to take it: For if he would wish to be known by this work
—and introduced to the best business and commissions for
instruments, from all parts of the continent,—his Orrery being placed
in our College, where so many strangers would have an opportunity
of seeing it, was the sure way to be serviceable to Himself.
“You will think, by all this, that I am offended with him, and that our
friendship may hereby be interrupted: Far from it—I went to see him,
the day the newspaper announced the affair. I soon found that I had
little occasion to say any thing: he was convinced, before I saw him,
that he had gone too far. But still, as no time was fixed for delivering
the Orrery, I was glad to find he had concluded that it should not be
delivered till next winter; against which time, he said, he could have
a second one made, if this one staid with him for his hands to work
by. As I love Mr. Rittenhouse, and would not give a man of such
delicate feelings a moment’s uneasiness, I agreed to wave the
honour of having the first Orrery, and to take the second.”
In fact, the Orrery was not at that time finished; for Mr. Rittenhouse
then informed Dr. Smith, that he was under the necessity of waiting
for brass from England, to enable him to complete it. “The result
(continued the Doctor) will be, I think, that he will keep his Orrery till
towards winter; and should they not then receive it, in the Jersies,
they will take it at New-York.”
On the 7th of the following month, Dr. Smith wrote thus finally, to
Mr. Barton, on this subject—“Your and my friend, Mr. Rittenhouse,
will be with you on Saturday. The Governor says, the Orrery shall not
go: he would rather pay for it, himself. He has ordered a meeting of
the Trustees on Tuesday next; and declares it as his opinion, that we
ought to have the first Orrery, and not the second,—even if the
second should be the best.”
158. The Rev. Dr. Peters wrote thus to Mr. Barton, under the date
of March 22, 1771—“Dr. Smith has done wonders in favour of our
friend Rittenhouse. His zeal has been very active: he has got enough
to pay him for a second orrery; and the assembly has given him
300l. The Doctor, in his introductory lecture, was honoured with the
principal men of all denominations, who swallowed every word he
said, with the pleasure that attends eating the choicest viands; and in
the close, when he came to mention the orrery, he over-excelled his
very self!”—“Your son will acquaint you with all the particulars
respecting it. The lectures are crowded by such as think they can,
thereby, be made capable of understanding that wonderful machine:
whereas, after all, their eyes only will give them the truth, from the
figures, and motions, and places, and magnitudes of the heavenly
bodies.”
159. The author of The Vision of Columbus, a Poem, (first

published at Hartford in Connecticut, in the beginning of the year
1787,) alludes to the Rittenhouse-Orrery, and to the numerous resort
of persons to the College-Hall, for the purpose of viewing that
machine, in the following lines, (book vii.)
“See the sage Rittenhouse, with ardent eye,
Lift the long tube and pierce the starry sky;
Clear in his view the circling systems roll,
And broader splendours gild the central pole.
He marks what laws th’ eccentric wand’rers bind,
Copies Creation in his forming mind,
And bids, beneath his hand, in semblance rise,
With mimic orbs, the labours of the skies.
There wond’ring crouds with raptur’d eye behold
The spangled Heav’ns their mystic maze unfold;
While each glad sage his splendid Hall shall grace,
With all the spheres that cleave th’ ethereal space.”
160. In a letter from Dr. Smith to Mr. Barton, dated March 23,
1771, is this paragraph:—
“I have been so busy these two months past, that I could not find a
moment’s leisure to write. A good deal of time was to be given to the
public lectures, the Orrery, and the getting our dear friend
Rittenhouse brought into as advantageous a light as possible, on his
first entrance into this town as an inhabitant; all which has
succeeded to our utmost wishes; and the notice taken of him by the
province, is equally to his honour and theirs. The loss of his wife has
greatly disconcerted him; but we try to keep up his spirits, under it.”
161. Joseph Galloway, Esq. was then speaker.
162. The committee, named in the above order of the general

assembly, made the following report to that body, on the 24th of
September, 1771; viz.
“The committee appointed to agree with, and purchase from Mr.

Rittenhouse a new Orrery for the use of the public, beg leave to
report, that they have, in pursuance of the order of assembly, agreed
with Mr. Rittenhouse for a new Orrery, at the price of four hundred
pounds, the price limited by the house; to consist of one principal
square (face,) of eight feet or more each way, with two wings;
making in the whole one large front, as nearly resembling the form of
the Orrery now standing in the College of the city of Philadelphia, as
its superior size will admit.” (Signed by all the members of the
committee.)
163. Messrs. Dickinson, Humphreys, Morton, Ross and Biddle,

together with Mifflin and Franklin, were delegated on the part of
Pennsylvania to the first general congress, which met in Philadelphia
on the 5th of September, 1774; and the same gentlemen, with the
addition of Messrs. Willing and Wilson, were also delegates from
Pennsylvania in the second general congress, which met in the
same city on the 10th of May, 1775. Of these “dignified and ever
memorable assemblies,” composed of that “illustrious band of
patriots whose worth sheds a lustre on the American character,” the
great Washington was also a member.
Mr. Dickinson, the writer of the celebrated Farmer’s Letters, was a

distinguished lawyer, statesman and scholar. Dr. Ramsay (who
published his History of the American Revolution at the close of the
year 1789,) remarks, that “the stamp-act, which was to have taken
place in 1765, employed the pens and tongues of many of the
colonists,” and, that “the duties imposed in 1767, called forth the pen
of John Dickinson, who in a series of letters, signed ‘A Pennsylvania
Farmer,’ may be said to have sown the seeds of the revolution.”
From the commencement of the momentous controversy between

the North-American colonies and the parent state, Mr. Dickinson was
an able and strenuous assertor of the rights of the colonists. In the
summer of the year 1768, the Rev. Mr. Barton sent him a little
artificial fountain or jet-d’eau, called a perpetual fountain, prettily
contrived and ornamented. On that occasion, the patriotic feelings of
Mr. Dickinson were thus expressed, in an handsome allusion to this
engine; feelings, called forth by some sentiments contained in the
letter which accompanied this small present,—“I wish” (said he, in
his answer to Mr. Barton’s letter, dated the 29th of August,)—“I wish
‘a perpetual fountain’ may water the tree of American liberty—I shall
always be ready and willing, with pious hands, to sprinkle its roots;
even though, for every drop of the pure element I throw upon them,
the free-booters should pour upon me all the foul waters in which
they delight to dabble. I have acted from the best of motives, the love
of freedom and of my country. If reproaches can influence the weak
and malicious, they never can blot from my memory the pleasing
consciousness of having endeavoured to do my duty. I am extremely
sensible of my own frailties; and yet I think I have so much charity,
that I reflect with pleasure, that perhaps these very people who
abuse me, may derive some little advantage from those very actions
of mine for which they abuse me. May heaven grant this to be the
case! It is all the revenge I desire to take of them; and this I think, my
good sir, is a Christian revenge.”
Messrs. Allen, Ross, and Biddle, shall be noticed in another place.
Mr. Sellers was a sensible and ingenious country-gentleman,

possessed of some skill in mathematical and astronomical science.
Messrs. John and Israel Jacobs (whose sister was the second wife
of Mr. Rittenhouse) were also well-informed country-gentlemen: the
former was speaker of the general assembly of Pennsylvania, and
the latter a member of congress, after the revolution. Mr. James
Wright was a very respectable representative of the county of
Lancaster, before the revolution. The gentlemen named in the
committee of the general assembly, to treat with Mr. Rittenhouse for
the purchase of an Orrery for the use of the public, were likewise
conspicuous for their worth. Of these, Mr. Rhoads was one of the
vice-presidents of the American Philosophical Society, and Mr.
Morton, a judge of the supreme court of Pennsylvania, before the
revolution: both were afterwards members of congress.
164. See Note 167.
165. Dr. William Cadogan’s “Dissertation on the Gout and all

Chronic Diseases,” &c. made its appearance in America about that
time; and the Rev. Mr. Barton, who had long experienced an
hereditary gouty affection, then thought favourably of the Doctor’s
general theory, although he could not adopt that ingenious theorist’s
doctrine, denying the existence of any hereditary diseases.

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Fundamentals of Cancer Prevention

Cancer Epidemiology and Prevention 4th Edition Michael

Halliday Resnick s Fundamentals of Physics 12e Extended

Esophageal Cancer Prevention Diagnosis and Therapy 2nd

Breast Cancer Fundamentals of Evidence-Based Disease

Fundamentals of construction estimating David J. Pratt

The Cancer prevention manual : simple rules to reduce

Essential Cell Biology Fifth Edition Alberts

Asphaltene Deposition : Fundamentals, Prediction,

ISBN 978-3-030-15934-4 ISBN 978-3-030-15935-1 (eBook)

© Springer Nature Switzerland AG 2019

First and foremost, I would like to pay tribute

I also want to thank all of the “Friends of the

University of Arizona Cancer Center

My collaborators and brilliant researcher

And finally, Heather Alberts my “wonder

Lisa M. Hess, PhD

I continue to thank my daughter, Rachael,

1 Introduction to Cancer Prevention���������������������������������������������������������� 1

12 Sunscreen-Based Skin Protection Against Solar Insult: Molecular

© Springer Nature Switzerland AG 2019 1

1.2 Overview of Cancer Prevention

1.3 Primary Prevention

The goal of primary prevention is to prevent a cancer from beginning to develop.

1.4 Secondary Prevention

1.5 Tertiary Prevention

8.00 % Any exercise

1.6 Molecular Approach to Carcinogenesis

Breast Atypical hyperplasia DCIS

The process of carcinogenesis involves multiple molecular events over many

1.7 Cancer Prevention Clinical Trials

The importance of conducting and participating in clinical trials cannot be under-

traditionally been unwilling to invest in the development of chemopreventive agents

increased risk of cardiovascular events after 18 months of cumulative administration

Balakrishnan M, George R, Sharma A, Graham DY (2017) Changing trends in stomach cancer

NCI 2018. https://www.cancer.gov/about-nci/budget/fact-book/data/program-structure

Stephen Joel Coons and Mira J. Patel

2.1 Introduction to Chapter

© Springer Nature Switzerland AG 2019 17

2.2 Outcome Assessment

2.3 Humanistic Outcomes

As mentioned above, humanistic or patient-reported outcomes (PROs) include a

symptomatic (e.g., pain intensity) to more complex aspects of functioning (e.g.,

• Physical health and functioning

In addition, disease- and/or treatment-related symptomatology (e.g., pain), gen-

“Permit me to repeat my earnest request, that you should be kind

“Dr. Rittenhouse, Pres. of the Am. Phil. Society.”

This really “interesting piece of furniture” was viewed by Dr.

The friendship that subsisted between Dr. Rittenhouse and Mr.

Mr. Jefferson has testified to the world the exalted opinion he

Mr. Jefferson retained the highest esteem for Dr. Rittenhouse,

“Monticello, Feb. 24, 1795.

“I am here immersed in the concerns of a farmer, and more

“Be so good as to present my best respects to Mrs. Rittenhouse;

“Chesnut Street, 15th June, 1795.

“Mr. B. begs leave to congratulate Mr. R. on this new honour, to

“David Rittenhouse, Esq.”

“Having the honour to transmit to you the Diploma of your election

“Charles Peter Layard.

The Royal Society of London has dealt out the honour of

Soon after Dr. Rittenhouse became associated with that illustrious

“Paris, at the College of France, May 14th, 1795.

“I have seen with great pleasure, in the transactions of your

1 Introduction to Cancer Prevention�� 1

12 Sunscreen-Based Skin Protection Against Solar Insult: Molecular

1.2 Overview of Cancer Prevention

1.3 Primary Prevention

1.4 Secondary Prevention

1.5 Tertiary Prevention

1.6 Molecular Approach to Carcinogenesis

1.7 Cancer Prevention Clinical Trials

2.1 Introduction to Chapter

2.2 Outcome Assessment

2.3 Humanistic Outcomes