Evaluation of Appeal and Impact of E-Cigarettes Among Chronic Smokers With Smoking-Related Cancers
Phase: NA
Conditions: Nicotine Dependence, Other Tobacco Product, Bladder Cancer, Lung Cancer, Cancer of Head and Neck
Sponsor: Dartmouth-Hitchcock Medical Center

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D15154: Evaluation of Appeal and Impact of E-Cigarettes  
Among Chronic Smokers with Smoking-related Cancers 
Dartmouth-Hitchcock Medical Center 
 
Principal Investigator: 
James D. Sargent, MD 
Co-Investigators: 
 
Konstantin Dragnev, MD 
 
 
 
 
Lionel Lewis, MA., MB BCh., MD., FRCP (London)  
 
 
 
 
Sarah Pratt, PhD 
 
 
 
 
Emily Scherer, PhD  
 
 
 
 
Alexander Fuld, MD  
 
 
 
 
Mary Brunette, MD 
 
 
 
 
Elizabeth Maislen, MD 
 
 
 
 
John Seigne, MD 
 
 
 
 
Nirav Kapadia, MD 
 
Address: 
Norris Cotton Cancer Center 
Dartmouth-Hitchcock Medical Center 
Geisel School of Medicine at Dartmouth  
One Medical Center Dr. 
Lebanon, NH 03756 
 
Initial protocol version:   
August 14, 2015 
Edited: 
 
 
October 27, 2015 
 
 
 
 
January 12, 2016 
 
 
 
 
March 31, 2016 
 
 
 
 
October 7, 2016 
November 4, 2016 
July 19, 2017 
August 18, 2017 

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Study Protocol Table of Contents 
 
Abbreviations 
3 
Abstract 
4  
Specific Aims and Hypotheses 
4  
Study Overview 
5  
Study Design Considerations 
5  
Study Design 
14  
Participants 
17 
Recruitment 
17  
Study Timeline and Follow-up 
18  
Outcomes Assessment 
18  
Statistical Analysis 
19 
Safety and Data Monitoring 
22  
References 
22 

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ABBREVIATIONS 
1-HOP 
1-hydroxy napthaline 
AJCC 
American Joint Committee on Cancer 
BMI 
body mass index 
CI 
confidence interval 
CO 
carbon monoxide 
CPSR 
Clinical Pharmacology Shared Resource of NCCC 
CTP 
Center for Tobacco Products at FDA 
DHMC 
Dartmouth-Hitchcock Medical Center 
DNA 
deoxyribonucleic acid 
DSMAC 
Data Safety Monitoring and Accrual Committee of NCCC 
ENDD 
electronic nicotine delivery device 
FDA 
Food and Drug Administration (U.S.) 
FEV1 
Forced Expiratory Volume in the first second 
FVC 
forced vital capacity 
g 
gram 
HPLC 
high performance liquid chromatography 
mg 
milligram 
mL 
milliliter 
NCCC 
Norris Cotton Cancer Center 
NF-kB 
nuclear factor-kappa B 
Ng 
nanogram 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNK 
nicotine-derived nitrosamine ketone 
NNN 
N′-nitrosonornicotine 
pmol 
picomoles 
ppm 
parts per million 
SPLC 
second primary lung cancer 
TLFB 
Timeline Follow-Back Questionnaire 
TSNA 
tobacco-specific nitrosamine 
US 
United States 

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ABSTRACT 
Smoking causes many cancers but also affects survival and quality of life. Currently, the 
only option available to smokers who present with cancer is to quit, a notoriously difficult 
undertaking. E-cigarettes represent a modified-risk tobacco product that could reduce 
toxicity and improve medical outcomes. We test the appeal of e-cigarettes in cancer 
patients that smoke, and the impact of their use on excretion of smoke-related toxic 
metabolites. This pilot study tests the feasibility of a larger randomized trial to examine the 
effect of e-cigarette use, on measures of smoke-related toxicity and medical outcomes. 
We will test feasibility in 40 smokers with aerodigestive tract cancers or bladder cancer, 
recruited over the course of nine months.  In this 12 week single-arm study, smokers will 
be recruited from oncology and surgical clinics that treat these cancers, supplied with a 
current generation e- cigarette product and will return to clinic every 3 weeks for 
assessments on their e-cigarette and cigarette use along with markers for toxicity from 
tobacco smoke inhalation. 
The overarching aim of the study is to determine the appeal of e-cigarettes as measured 
by the degree to which smokers with cancer adopt their use over the 9 weeks they are 
supplied with product. We will measure past use of e-cigarettes and cigarettes at baseline, 
3, 6, 9, and 12 weeks. We will also assess the effect of e-cigarette substitution on toxicity 
by measuring expired carbon monoxide and urine NNAL, a carcinogenic metabolite of 
cigarette smoke. This translational research involves a multi-disciplinary team of 
prevention scientists, tobacco-use experts, statisticians, cancer clinicians, and 
psychiatrists and uses NCCC and White River Junction VAMC statistical and clinical trials 
resources. 
 
SPECIFIC AIMS AND HYPOTHESES 
Aim 1: To evaluate the behavioral and psychological appeal of e-cigarettes among 40 
chronic smokers with smoking-related cancers. 
Hypothesis 1 (H1): Greater than 50% of study participants will report daily e-cigarette use 
at each assessment during the 9 weeks that e-cigs are provided, and mean satisfaction 
with e- cigarettes will be >4 on a 5-point scale. In a parallel process growth model for e-
cigarette and cigarette use, there will be a significant negative correlation of growth slopes. 
Aim 2: To evaluate the effect of e-cigarettes on biological markers of combusted tobacco 
toxicity. 
Hypothesis 2 (H2): After 9 weeks, mean expired breath CO2 and urine NNAL will be 
reduced. 
 
Primary outcomes: 
Appeal (H1)—E-cigarette use and amount of e-cigarette product used per week, 
proportion of participants that report e-cigarette use at each assessment, satisfaction 
scores for e-cigarettes, and whether they continue e-cigarette use at 12 weeks (3w after 
end of trial). Correlation between change in e-cigarette use and change in cigarette use. 

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Combustible Tobacco Toxicity (H2)—Exhaled CO, urine NNAL and 1-hydroxy napthaline 
(1- HOP). Because smokers are good at regulating nicotine intake, we expect no change 
in urine cotinine over time. 
 
STUDY OVERVIEW 
This pilot study will test the appeal and toxicity of e-cigarettes as a substitute for cigarettes 
among smokers with aerodigestive tract cancers or bladder cancer. Participants will 
receive e- cigarettes for 9 weeks and be asked to substitute the e-cigarette product for 
their usual combustible product. Primary outcomes include e-cigarette appeal, e-cigarette 
use/satisfaction and combustible tobacco toxicity. 
 
STUDY DESIGN CONSIDERATIONS 
INTRODUCTION 
Smoking is responsible for $130 billion in direct healthcare expenditures and half a million 
deaths every year in the United States, primarily from cancers, cardiovascular disease and 
chronic lung disease. The most recent Surgeon General report added new causal 
associations between active smoking and age-related macular degeneration, diabetes, 
colorectal cancer, liver cancer, adverse health outcomes in cancer patients and survivors, 
tuberculosis, erectile dysfunction, orofacial clefts in infants, ectopic pregnancy, rheumatoid 
arthritis, inflammation, and impaired immune function.4  Of all the preventable causes of 
disease, smoking ranks by far as the most important single modifiable risk factor because 
it remains a prevalent behavior (affecting about 20% of the population), because of its 
strong relation to many disease outcomes, and because of its lack of specificity: Smoking 
is linked with almost every important chronic disease. 
 
SMOKING AS A CAUSE OF CANCER 
Among all modifiable risk factors for cancer, cigarette smoking exerts the greatest single 
effect, being responsible for about one-third of cancer deaths.5 With respect to cancer, 
cigarettes deliver dozens of toxins to the lung in the tar component of smoke, where they 
are absorbed into the surrounding tissues and transmitted to other tissues through the 
blood stream. Figure 1 illustrates the known mechanisms that relate continued exposure to 
these toxins and the onset and development of cancers. Tobacco smoke contains more 
than 7,000 chemicals, and at least 69 of these can cause cancer.6 These carcinogenic 
compounds deposit in the lung tissues and act locally, and are transmitted through the 
circulatory system to tissues remote from the lung. 
For example, N-nitrosodimethylamine, and 4-aminobiphenyl are liver metabolites 
implicated in the association between smoking and cancer of the liver.4 Other metabolites, 
e.g. urinary 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), N′-nitrosonornicotine 
(NNN), and their glucuronide metabolites of the tobacco-specific nitrosamine (TSNA), 
nicotine-derived nitrosamine ketone (NNK), are subsequently concentrated in the kidney, 
leading to high organ exposure in those tissues and the bladder. 
Some constituents (or metabolites) of tobacco smoke bind to cellular receptors and 

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activate protein kinases and growth receptors, which can induce inflammation,7  resulting 
in enhanced pneumocyte proliferation, activation of nuclear factor-kappa B (NF-kB), and 
tumor promotion.8 These same mechanisms could affect tumor growth rates after 
diagnosis and risk of secondary recurrence after successful treatment of the primary 
tumor. 
 
 
 
The main addictive component in tobacco, nicotine, has little toxicity in cigarette doses, 
especially to smokers, who are tolerant to its effects on the brain and other systems. 
Nicotine is also available from various nicotine replacement products that have been found 
to reduce cigarette consumption when given to active smokers.9 
Reviews of studies have found that this approach does not reduce the chances that a 
smoker will quit smoking.10 Moreover, smoker titrate their nicotine intake when given 
multiple nicotine products, such that urine cotinine levels remain the same when smokers 
are given a nicotine replacement product.11 More recent unpublished data show that 
introduction of e-cigarettes in smokers does not result in rises in saliva cotinine, but is 
associated with changes in cigarette consumption.12 
 
SMOKING AMONG CANCER PATIENTS 
Given the prominent role smoking plays in carcinogenesis, it is not surprising that smoking 
is more common in cancer patients than in the general population. In a cohort of 5185 
recently diagnosed cancer patients at Roswell Park Cancer Center,1  62% of all patients 
had  some involvement with tobacco during their lives: current smokers (18%), recent 
quitters (10%), or former smokers (35%). Cancers with the highest rates of current 

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smoking included head & neck (29%), bladder (27%) and lung (24%).13 Another study 
summarized cross-sectional and longitudinal studies of smoking after cancer diagnosis 
among lung and head & neck cancer patients, and found an overall rate of 33%.14 
Summary of the longitudinal studies in this review found little evidence to support the 
notion that cancer patients who smoke tend to quit over time. There were few studies of 
level of addiction among cancer patients that some, but given their life circumstances and 
the lack of evidence for quitting, it would be reasonable to conclude that these individuals 
are heavily addicted smokers that would be expected to be relatively refractory to 
treatment and for whom alternatives to cessation should be considered. 
 
OUTCOMES FOR SMOKING-RELATED CANCERS IN SMOKERS VS. FORMER 
SMOKERS  
EFFECT ON MORTALITY 
In the Roswell Park study investigators assessed smoking status for 5185 cancer patients 
enrolled into treatment programs between 1982 and 1998.1  Survival curves like the one in 
Figure 2 compared survival by disease site for current vs former smokers/recent quitters. 
Not all the curves are as striking as this one, which shows overall survival for head & neck 
cancer, but continued smoking was an important risk factor for many cancers and overall, 
with adjusted hazard ratio for time to mortality being 1.29 (95% CI 1.17, 1.42) for current 
vs. former smokers and 1.18 (1.04, 1.33) for current vs. recent quitters after adjusting for 
grade and stage, age, BMI, and several other risk factors. Given that many of the recent 
quitters would have relapsed (see below), the increased survival in recent quitters 
represents a possible harm reduction influence conferred by decreased daily cigarette 
consumption.  Furthermore, a systematic review of observational studies examining the 
influence of smoking cessation after diagnosis of early stage lung cancer suggested that 
the mortality benefit seen with smoking cessation was due more to reduced cancer 
progression rather than fewer cardiorespiratory deaths.15 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 1 

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EFFECT ON RISK FOR SECOND PRIMARY CANCER 
Other studies have looked specifically at how smoking status relates to the probability of 
developing a second primary. A study of over 1484 patients with a primary non-small cell 
lung carcinoma (median follow-up 26 months) found that 66 developed a second primary 
lung cancer (SPLC).16 Among smokers the only variable associated with SPLC 
development was smoking pack-years (entered as a continuous variable), with hazard 
ratios indicating an 8% increase in risk for SPLC development for each additional 10 pack-
years.  A much larger prospective study17 pooled data from five prospective cohorts, 
examining hazard of developing second primary cancers and compared never-smokers 
with former smokers <20 cigarettes per day, former smoker > 20 cigarettes per day, 
current smoker < 20 cigarettes per day, and current smoker ≥ 20 cigarettes per day.  Table 
1, adapted from the study, shows hazard ratios for second cancer development for lung, 
bladder, kidney, and head/neck cancers.  Compared to never smokers, higher levels of 
former and current smoking showed substantially greater hazard of second primary 
cancers in all categories, with current smokers having higher risk compared to former 
smokers.  Note the finding of a dose-response among smokers, showing consistently 
higher hazard ratios for those who smoked ≥ 20 cigarettes per day vs. those who smoked 
less. This adds justification to the idea that e-cigarette substitution could improve cancer 
outcomes even if the smoker was not able to achieve complete substitution of the e- 
cigarette product. 
 
 
 
ONLY A SMALL PROPORTION OF CANCER PATIENTS SUCCEED AT 
QUITTING SMOKING 
The information from the Roswell Park study would suggest that approximately 30-40% of 
smokers attempt to quit at or around the time of their cancer diagnosis. A recent 
publication from a large, well-funded cessation service at Sloan-Kettering18  offering 
intensive cessation support, found that of over 4500 tobacco user referrals, 3430 (75%) 
were unreachable or refused cessation assistance. Of the over 1000 enrolled in the 
service, about 25% did not complete the protocol, 25% either died or were lost to follow-
  
 e
 
 
 
 
 
 
 
 
 
 
 
p
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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up, and 43% reported no tobacco use at 6 months. In summary, the data from a large 
cessation service at a major cancer center suggest that these state-of-the art programs 
benefit only about 10% of smokers with cancer.  This is, again, consistent with the findings 
above that suggest these individuals are heavily addicted and relatively refractory to 
cessation treatment, leaving about 90 percent who continue to expose themselves to 
smoke-derived carcinogens during the course of their therapy. 
The Sloan-Kettering program assessed e-cigarette use among patients trying to quit 
smoking and found that as many as half of these patients were experimenting with e-
cigarettes during 2013, but that e-cigarette use did not affect successful quit rates. This is 
becoming a common finding in population studies of e-cigarettes, in part because people 
receive mixed messages from the public health community regarding whether these 
products represent an appropriate substitute for smoking. In the present study, we will test 
the appeal and toxicity of e-cigarettes in smokers with cancer. 
 
E-CIGARETTES 
WHAT ARE THEY AND HOW DO THEY WORK 
Electronic cigarettes, also known as e-cigarettes, create an inhalable nicotine aerosol by 
heating a liquid nicotine solution.  Unregulated in the US, e-cigarette sales have seen a 
rapid rise unparalleled by any other non-combustible nicotine delivery system.19  The main 
components of the e-cigarette include a battery, a cartridge with nicotine dissolved in 
propylene glycol or vegetable glycerol, and a heater that aerosolizes the nicotine—
propylene glycol solution. When the user puffs on the end of the device and creates a 
vacuum, the battery powers the heater and creates aerosol, which is drawn into the mouth 
piece and inhaled (Figure 3). E-cigarettes come in many styles and are rapidly evolving. 
This was true for first gen e-cigs. Later models have a button to push on the battery, which 
creates a bolus of vapor ready for immediate inhalation when the e-cig reaches the mouth. 
 

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THEORETICAL CASE FOR E-CIGARETTE HARM REDUCTION IN SMOKERS 
WITH CANCER 
TOXICOLOGY 
E-cigarettes are not currently regulated, and the Food and Drug Administration has 
required no information from manufacturers on their ability to deliver nicotine and potential 
toxicity. 
However, compared to cigarettes, they should deliver comparatively fewer toxic chemicals 
to the lung; available evidence strongly suggests this is true.  Compared to tobacco 
smoke, studies have found e-cigarette smoke to be substantially lower in toxic content, 
cytotoxicity, and adverse side effects.20   One laboratory study comparing the toxicity 
profile of e-cigarette aerosols and tobacco smoke found that known tobacco toxins in e-
cigarette aerosols were 100 to 1000 times lower than those found in tobacco smoke.21 
Another FDA study found that carcinogenic tobacco specific nitrosamines in e-cigarette 
vapor was 8.2 ng/g, similar to the level in nicotine patch users (8.0 ng/g) and much less 
than the level in Marlboro cigarette smoke (6260ng/g).22 Another study found that toxic 
metabolites of cigarette smoke were greatly reduced in the urine of e-cigarette users 
compared to smokers.23 
Studies have also reported that e-cigarette use had no inflammatory effect on complete 
blood count indices,24 nor did it cause significant reduction in lung function (3% reduction 
FEV1/FVC) compared to cigarette smoke (7% reduction FEV1/FVC),25 and that e-
cigarette use had no negative effects on myocardial function.26 Based on these and other 
studies, Public Health England has published a public statement that e-cigarettes are 95% 
safer than smoking.27 
Although e-cigarettes appear to have much lower toxic potential compared to cigarettes, 
 
  
 
 
 
 
 
 
 
 
 
 
 

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and are being embraced by some public health programs, they are not free from toxicity.  
Because of the lack of regulation of these products, we are now faced with an array of 
products, and no standardization of nicotine concentration, flavoring, and contaminant 
allowance.28 Lipoid pneumonia has been reported in one e-cigarette user, probably as a 
result of flavoring oils or oil contaminated glycerol.29 Use of high voltage batteries in 
refillable tank devices converts propylene glycol at very high temperatures to 
formaldehyde, but not to the levels found in tobacco smoke.30   Data are starting to appear 
that suggest that some of the flavor components of e-cigarettes may affect lung epithelial 
cells and inflammation,31 and even nonflavored vapor affected macrophage-moderated 
inflammation in mice exposed to the vapor.32 Thus, the sum of the limited data available 
so far suggests that, compared to cigarette smoke, e-cigarette vapor exposes users to 
much lower levels of toxins. While it remains unknown what the impact on health or 
oncological outcomes of e-cigarettes may be, the factors outlined above suggest a clear 
theoretical safety advantage over continued use of combustible tobacco products for 
patients with cancer. Given almost universal access to these products and the fact that 
cancer patients are using them, we have an obligation to determine how they affect 
consumption of combustible tobacco and whether their use affects intermediate medical 
outcomes. That is the overarching purpose of the present research. 
 
NICOTINE DELIVERY 
Much of the nicotine from cigarettes is delivered to the brain by arterial circulation within 
seconds of puffing on the cigarette.33 This is one of the reasons for high abuse liability for 
cigarettes. Nicotine delivered from the oropharynx (e.g., when smokeless or nicotine gum 
is used) enters the venous blood and passes through the liver before going to the brain. 
This not only delays its delivery to the brain, but it lowers the dose because some of the 
nicotine is changed to cotinine in the liver. For e-cigarette aerosols, about half the nicotine 
absorbed is delivered through the alveoli, with the other half being delivered to the venous 
circulation through absorption from the oropharynx and bronchial tree.34 Delivery of 
nicotine is improving as e-cigarette manufacturers improve design. First generation e-
cigarette devices, released between 2008 and 2010, delivered nicotine primarily to the 
mouth and oropharynx and could not product plasma nicotine concentrations equivalent to 
cigarettes (blue line in Figure 4 below). 
Nicotine absorption from new generation devices (produced after 2010, red line in Figure 
4) are able to equivalent levels of plasma nicotine, but only after 20-30 minutes of puffing.2 
However, nicotine delivery from e-cigarettes has been shown to improve with practice,35 
and more recent studies find that experienced users of some products can quickly deliver 
cigarette-like nicotine doses.36 
 

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BEHAVIORAL ADVANTAGES 
Despite some disadvantages of nicotine delivery compared to cigarettes, e-cigarettes 
represent an improvement in nicotine delivery compared to available nicotine replacement 
products, such as nicotine gum or patch, products that were intentionally meant to be 
slowly absorbed.35  Part of the appeal of the e-cigarette is in how it mimics the behavioral 
process of smoking. The importance of the behavior in maintaining the smoking habit was 
recognized over 30 years ago by chief Philip Morris scientist William Dunn, who stated, 
“The smoking act has many dimensions. The motor aspects, drawing the smoke into the 
mouth, inhaling the smoke into the lungs … taste and olfactory sensations are elicited, 
sensations are elicited when the smoke is drawn down into the lungs, psychosocial 
symbolism is imparted to the person, and a large number of chemical compounds pass 
rapidly into the bloodstream.”37 Nicotine replacement therapy emphasizes the effects of 
one of those compounds and largely ignores the important behavioral aspects of the habit.  
The effect of the behavioral components of the e-cigarette are apparent in a study of e-
cigarette use and cigarette craving.3   As illustrated in Figure 5 below, e-cigarette use was 
associated with substantial reductions in cigarette craving, and these immediate 
reductions were independent of whether the device contained nicotine. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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a 
 
 
E-CIGARETTE REGULATION: IMPLICATIONS ON STUDY DESIGN 
As detailed below, the specific aims of this project are to determine the appeal and 
toxicity of e-cigarettes in current smokers with a smoking-related cancer. This is NOT a 
smoking cessation study; instead, it examines changes in intake for two tobacco products 
when administered together. There is a regulatory basis for the decision to focus on 
appeal and toxicity, and not smoking cessation. When e-cigarette devices first attempted 
to enter the US market, the Food and Drug Administration (FDA) blocked shipments on 
the basis that e-cigarettes were unapproved drug delivery devices and must first pass 
through FDA’s New Drug Application process before they could be legally sold. E-
cigarette manufacturers sued, arguing that e-cigarettes contained nicotine derived from 
tobacco and were therefore a tobacco product; the US Court of Appeals (Washington DC) 
ruled in their favor; and the FDA decided not to seek further review. The FDA then 
determined that they would “deem” e-cigarettes to be covered under the Family Smoking 
Prevention and Tobacco Control Act (deeming is in process at this date). In the meantime, 
the FDA has determined that any evaluation of the e-cigarette product for a therapeutic 
endpoint (such as treating nicotine addiction) requires an Investigational New Drug 
Application (involving animal pharmacology and toxicity studies, manufacturing information 
on the product, etc.).  This regulation does not allow scientists not closely affiliated with an 
 
Figure 5. Craving to smoke a cigarette as a function of time and whether the 
smoker was inhaling a cigarette or an electronic nicotine delivery device (ENDD) 
with and without nicotine or a nicotine inhaler (one form of nicotine replacement 
therapy). Taken from Bullen, et al. 3 

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e-cigarette company to study these products as therapeutic devices.  Moreover, e-
cigarette companies have made it clear in US courts that they do not seek approval as a 
drug delivery device. 
The Center for Tobacco Products (CTP) at FDA is charged with regulating the tobacco 
market under the Family Smoking Prevention and Tobacco Control Act, which charges the 
FDA, among other things, “to promote cessation to reduce disease risk and the social 
costs associated with tobacco-related diseases.”  CTP funds investigators to help the 
agency compare tobacco products with respect to three issues of interest—their relative 
appeal, toxicity, and effect on health. This leaves scientists the option of studying the e-
cigarette as a modified risk tobacco product in smokers with respect to those three types 
of outcomes.  The ultimate goal is to reduce the harm caused by cigarettes and other 
combustible tobacco products by substituting less toxic delivery devices for the primary 
drug, nicotine.  This pilot project begins this line of investigation with a short-term study of 
e-cigarette appeal and toxicity among cancer patients that smoke. 
 
TRIAL PROTOCOL 
STUDY DESIGN 
We will enroll 40 chronic smokers from the Norris Cotton Cancer Center and the White 
River Junction VAMC, approximately 15 of which will be accrued from the White River 
Junction VAMC.  Participants will be given access to e-cigarettes for a 9-week period. 
Consecutive patients with stage I-IV aerodigestive tract cancers or bladder cancer who 
are current daily smokers will be identified two ways: 
1) Clinic Recruitment - Potential participants will be identified by the treating physician 
during routine clinic visits. Patients will be advised to quit smoking as per the 
standard of care. Any patient wishing to quit smoking will be referred for smoking 
cessation counselling through the DHMC program, the White River Junction VAMC 
program, or their state help-line. Once eligibility is confirmed and informed consent 
is obtained and signed, patients will be enrolled in the study. 
2) EMR Recruitment: In a recruitment strategy that parallels clinic recruitment, we will 
use the EMR to identify all potentially eligible smokers (with the diagnosis of 
aerodigestive tract cancers or bladder cancer) that have been seen in the NCCC in 
the past 3 years.  EMR records will be searched by the D-HRDS Analytics Institute 
who will then forward a list of potential subjects to the project coordinator with their 
diagnoses and contact information, consistent with our partial HIPAA waiver.  The 
project coordinator will then send this list of potential subjects to their providers to 
be approved to be contacted about the study.  Approved potential subjects will then 
be contacted by mail through a letter from their NCCC oncology group.  The 
subjects will have an opportunity to opt out of receiving a phone call through a 
prepaid return mailer or by calling a telephone number.  If we do not hear from 
them in 2 weeks, we will then attempt to call them.  We will attempt to call one time 
a week for 3 weeks.  If there is no answer we will leave a brief, generic message.  
The call will assess their smoking status, and their willingness to quit.  Nonsmokers 
are not eligible.  If they smoke and are interested in quitting, they will be referred to 
their state quit line.  If they are not interested in quitting at this time, they will be 

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offered participation in the study, and we will confirm eligibility.   The mailing will 
include:  A letter from their oncology group at NCCC, the brochure for their state 
quit line, a handout about the study, and a paper to return to us in a postage-paid 
envelope.  If they return the paper to us requesting a referral to the quit line we will 
notify the D-H smoking cessation specialist. He/She will then process the referral to 
the quit line in EDH.  The patient will then be contacted directly by the quit line.  We 
will also provide them with their state smoking cessation help-line numbers.  If they 
return the paper to us indicating they do not wish to quit and would like more 
information regarding the study, a coordinator will contact them. 
Once enrolled, participants will receive the e-cigarette product described below, will be 
instructed on use of the e-cigarette, and given a supply that is approximately equivalent to 
their current nicotine intake.  They will be told that e-cigarettes are theoretically safer than 
cigarettes, and that this trial aims to test how appealing the product is for smokers not 
willing to quit consuming nicotine. 
We have opted to use e-cigarette products produced by Halo, a US manufacturing 
company that emphasizes the purity of its products and its approach to quality control in 
the manufacturing process. Patients will be given Halo Triton, which uses a leak-proof 
refillable tank system that has had a recent technological update.  The patient will be 
shown how to fill the tank and will be observed filling it.  Those not able to manage the 
tank refill will be given Halo G6 leak proof prefilled cartomizers (the part of the e-cigarette 
that contains the nicotine solution and the heating filament); these can be substituted for 
the tank on the Triton battery.  The starter kit that will be distributed to patients is 
illustrated in Figure 6. 
HALO manufactures its e-cigarette and the nicotine solutions in the United States. The 
HALO solution e-cigarettes contain 0, 12, 18, 24, or 36 mg/ml nicotine. We have been 
advised to begin our participants with 18mg/ml and move up or down based on patient 
preference. E-cigarette liquid also comes in many flavors, and we have decided to allow 
participants to choose from four options.  Halo has agreed to provide us with the names of 
their 4 highest selling liquids.  They have shared an ingredients list with the Drs. Sargent 
and Lewis for the purposes of adverse event monitoring and in the event that our IRB 
members request information about the ingredients. 

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T 
 
 
Coordinators will assess participants at baseline and weeks 3, 6, 9, and 12.  Although 
most of our patients are expected to have completed their therapy, the schedule is 
designed to integrate with return schedules for many chemotherapeutic regimens, if 
possible. We have considered the concern that chemotherapy could affect cigarette 
consumption or excretion of nicotine metabolites. According to our clinicians, the current 
chemotherapy regimens for these cancers are not associated with severe symptoms, such 
that patients rarely decrease their smoking during treatment. Nevertheless, we will assess 
the severity of 6 common chemotherapy side effects at each visit so that may be entered 
as a covariate in our analytic models. Regarding metabolites, for nicotine, the major 
metabolite cotinine is formed via CYP2A6 and CYP2B6 metabolism, and the traditional 
cytotoxic chemotherapeutic agents used in the cancer treatment are not known to affect 
the activity of these CYP450 /UGT enzymes significantly. Additionally, cyclical cytotoxic 
chemotherapy is not given every day throughout a cycle. The most well characterized 
carcinogens of smoking so far are NNK (4-(methylnitrosamino)1(3-pyridyl)-1-butanone) 
and NNAL (4-(methylnitrosamino)1(3-pyridyl)-1-butanol). These carcinogens are also 
metabolized by some of the same enzymes that metabolize nicotine including CYP2A6, 
UGT2B10, UGT1A4 and CYP2A13, so these should not be affected by most 
chemotherapeutic regimens. 
Coordinators will assess eligibility, collect specimens, administer CO2 measurements and 
administer the surveys during the baseline and follow up visits. 
 
 
   
 
 
 
 
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PARTICIPANTS 
Inclusion Criteria: 
1) Histological or cytological diagnosis of aerodigestive tract cancers or bladder 
cancer within the past 5 years (more than one tobacco-related malignancy is 
allowed) 
2) AJCC stages I-IV 
3) Daily smoking (at least 10 cigarettes per day for 10 years) and breath CO2 ≥8 ppm 
4) Does not wish to quit smoking now (anyone wishing to quit smoking will be referred 
for smoking cessation counselling through the WRJ VAMC or DHMC program) 
5) May be receiving anti-cancer agents 
6) Age 18 or older 
7) Fluent in English 
8) Patient must be capable and willing to provide informed written consent for study 
participation 
9) Able to participate in study visits 
 
Exclusion Criteria: 
1) Cancer surgery planned in the next 9 weeks 
2) Treatment with radiation planned for the next 9 weeks 
3) Actively trying to quit smoking, or planning to in the next 30 days. (If a subject 
reports that they plan to quit smoking in the next 30 days, we will call them after the 
30 days to see if they are still trying to quit.) 
4) Any use of e-cigarettes in the past 30 days 
5) Pregnant or trying to get pregnant 
 
RECRUITMENT 
Potentially eligible patients will be identified by clinician-researcher collaborators and 
through clinical trials nurses or clinical research coordinators, who monitor the cancer 
patient population for recruitment into clinical studies. Patients may be identified in 
multiple clinical settings, including outpatient clinics and the infusion suite. Once a 
potentially eligible patient is identified, a referral will be made to the site coordinator, who 
will meet with the patient, confirm eligibility, and obtain consent for the patient to 
participate in the study, and register the patient in the Velos e-Research database. (If a 
site coordinator is unable to utilize Velos, that coordinator will submit participant data to 
another coordinator with access and it will be entered into the Velos e-Research 
database.)  The coordinator will conduct baseline web assessments, provide e-cigarettes 
and instruction on how to use the product, and conduct all follow up assessments. 
 

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STUDY TIMELINE AND FOLLOW-UP 
The trial is designed to allow for patient visits every 3 weeks for 12 weeks. The 
coordinators will work with the participant and the participants’ medical care teams to 
schedule and conduct the visits. We will contact enrolled subjects for follow-up at 6 and 12 
months after enrollment.  Each time, we will attempt to contact the subjects 3 times by 
phone over a period of 3 weeks.  During the call the subject will be asked if they are still 
using an e-cigarette, what brand they are using, what concentration of nicotine they use, 
how many times a day they use it, and how often they currently smoking any combustible 
tobacco products. 
Participants will receive free e-cigarette products for the first 9 weeks of the trial and $20 
for each visit ($100 total). Participants that travel more than 20 miles one-way for a study-
only visit (no other appointments scheduled on the day of their study visit) will be given a 
$10 gas card. 
 
Table 2. Timeline for study activities and compensation 
Time 
Baseline 
3 weeks 
6 weeks 
9 weeks 
12 weeks 
Activity 
Consent; survey; ecig 
instruction; urine; CO 
Survey; ecig refill; 
urine; CO 
Survey; ecig refill; 
CO 
Survey; 
qualitative 
interview; urine; 
CO 
Survey; 
CO 
Compensation $20 
$20 
$20 
$20 
$20 
 
OUTCOMES ASSESSMENT 
Each visit will include a checklist that assesses how the participant is using the e-
cigarettes and what problems he/she may be encountering with the use of the e-cigarette 
device. Adverse events will be assessed with a checklist for commonly occurring side 
effects from e-cigarettes and nicotine products. The coordinators will conduct and audio-
record a 10-15 minute qualitative interview at 9 weeks soliciting perceptions about e-
cigarettes to be transcribed and analyzed for common themes that could be useful in 
developing the larger intervention. 
Behavioral assessments: We will use a Timeline Follow-Back Questionnaire (TLFB)38,39 
to document use of cigarettes at baseline and cigarettes/e-cigarettes at baseline, 3, 6, 9, 
and 12 weeks. At follow up visits participants will be instructed to bring in all used and 
unused e- cigarettes, in order to verify reports of e-cigarette use. We will evaluate appeal 
with attitudinal ratings, on a 5-point Likert-type scale, e-cigarette ease of use, satisfaction, 
and enjoyment, and willingness to continue to purchase e-cigarettes in the future. All 
questionnaires are being programmed using a secure web-based system set up and 
maintained by the Dartmouth Bioinformatics group led by Kristen Anton. 
Biomarkers of behavior: Cigarette smoking will also be measured with exhaled carbon 
dioxide. We will assess expired breath CO2 using Micro Smokerlyzer meters (Bedfont 
Scientific), which have already been purchased for a previous study. The protocol will 
follow operating instructions that come with the devices, and the devices will be calibrated 
weekly with 40PPM CO2/air mixture. E-cigarette smoking will be measured with urine 
propylene glycol, the main constituent of e-cigarette aerosol. Some 40% of ingested 

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n 
propylene glycol is excreted unchanged in the urine. 
The NCCC Clinical Pharmacology Shared Resource (CPSR) will conduct assays of urine 
for smoke-related carcinogens. Urine samples (at least 20 mL) will be collected at the 
study defined time points from study participants in standard urine containers. These will 
be delivered to the NCCC CPSR, divided into 5 mL aliquots and stored at -20°C or below 
until analysis. Urine aliquots will be assayed in batches based on the published assays 
for urine nicotine, cotinine, 4- (methylnitrosamino)-1-(-3pyridyl)-1butanol (NNAL)40 and 1-
hydroxy naphthalene (1-HOP)41 concentrations. These assays can and will be 
established and validated in the NCCC CPSR using the LC-MS/MS and HPLC-
Fluorescence services available in the CPSR. 
 
STATISTICAL ANALYSIS AND POWER CONSIDERATIONS 
Qualitative Analysis 
A follow up interview will be conducted at week 9. The interview will be transcribed and a 
thematic analysis will be conducted to evaluate common issues encountered by smokers 
with cancer patients who use e-cigarettes. Thematic analysis consists of examination of 
text by identifying and grouping themes, followed by coding, classifying, and developing 
categories. Transcripts are uploaded into a qualitative analytic software program and 
analyzed using Atlas.ti, a qualitative coding program. Co-investigator Sarah Pratt has 
experience using similar qualitative methods to interview health professionals. She will 
supervise the coders, staff at the Centers for Health and Aging at Dartmouth who have 
been trained to perform similar analyses in other studies. 
Substitution assessment: The proportion of participants who report use of e-cigarettes 
during each follow-up visit during treatment will also be computed (along with a 95% 
confidence interval).  This proportion is expected to be at least 0.5.  With 40 participants, 
width of a 95% confidence interval around this proportion will be at most 0.32. The 
satisfaction with e- cigarettes (averaged across 3 treatment assessments) will be 
summarized among participants using descriptive statistics and the amount of e-cigarette 
product returned at each follow-up period will be summarized across the treatment period. 
To explicitly test the substitution/replacement mechanism of e-cigarettes, we will perform 
an exploratory parallel process growth model fit within a structural equation modeling 
framework.42 In this model the trajectory over time of both frequency/quantity of cigarette 
use and frequency/quantity of e-cigarette use will be modeled assuming individual-level 
latent intercept and slope (i.e., latent growth curve model). A significant negative 
association between the latent slope of e-cigarettes and the latent slope of combustible 
cigarettes would be consistent with the replacement/substitution hypothesis. The model 
provides an explicit statistical test of the hypothesis that, as e-cigarette usage increases, 
combustible cigarette usage decreases. Power for this analysis is computed as that for an 
individual-level correlation coefficient assuming 40 participants. There will be at least 80% 
power to detect a correlation that is at least -0.4 between these two individual-level slopes. 
Figure 7 shows a diagram of the parallel process growth model. 
 

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Toxicity Assessment: Our measures of toxicity, urine NNAL, 1-HOP and CO2 will be 
compared between the baseline and 9-week assessments via paired t-test. For NNAL, 
assuming a standard deviation of change in this measure of 3.8 pmol/mg creatinine (as 
was seen in Joseph et al. 2008), with 40 participants, this test will have 80% power at the 
two-sided 0.05 significance level to detect a change from baseline of 1.7 pmol/mg 
creatinine.  There is not enough information available on 1-HOP to perform a test of 
power, so analysis of this metabolite is considered exploratory. For expired CO, assuming 
a standard deviation of change in this measure of 17.0 ppm,43 with 40 participants, a 
paired t-test comparing baseline to 9-week will have 80% power at the two-sided 0.05 
significance level to detect a change from baseline that is 7.7 ppm. Additionally, since CO2 
will be measured several times throughout the treatment period, the trajectory of change 
over time in this measure will be modeled via linear mixed effects models including 
random intercept and slope terms to account for repeated observations within individual. 
With repeated measurements of CO, the power for the mixed model will be greater than 
that of the paired t-test of change from baseline to detect this change over time. 
We will also evaluate toxicity by analyzing cotinine level to assure that the adverse effect 
of increased cotinine (resultant from increased e-cigarette usage without similar decrease 
in combustible cigarettes). To do this, we will compute the number of participants with an 
increase in cotinine over the course of the study and consider this an adverse event. With 
40 participants, confidence intervals around this adverse event percentage will be at most 
0.32 percentage points. The table below gives the probability of observing at least 1 
participant with an increase in cotinine given different true percentage of participants with 
this adverse event. For example, if the population-wide true percentage of participants 
with cotinine increase is 0.5%, then the probability of observing at least 1 of the 40 study 
participants with an increase is 0.18. 
   
 
 
 
 
 
 
 
   
 
 
 
 
n
  
 
 
 
 
 
 

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True percentage of participants with 
increase cotinine 
Probability of observing at least 1 adverse 
event (increase in cotinine) 
0.5% 
0.18 
1% 
0.33 
2% 
0.55 
5% 
0.87 
10% 
0.99 
 
 
ON-SITE MONITORING 
Clinical research monitoring for regulatory compliance and data integrity will be conducted 
according to the NCI-approved NCCC Data and Safety Monitoring Plan. Internal 
monitoring is conducted by appropriately trained staff of the NCCC Office of Clinical 
Research and Dartmouth-Hitchcock Medical Center Clinical Trials Office (CTO) and the 
White River Junction VA Medical Center who are not involved in the study. This 
monitoring will include periodic assessment of the regulatory compliance, data quality, and 
study integrity. Study records will be reviewed and directly compared to source documents 
and the conduct of the study will be discussed with the investigator. Monitors may request 
access to all regulatory documents, source documents, CRFs, and other study 
documentation for on-site inspection. Direct access to these documents is guaranteed by 
the investigator, who must provide support at all times for these activities. 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable Dartmouth research compliance and 
quality assurance offices. The investigator will permit study protocol related audits and 
inspections by the Dartmouth CPHS, government regulatory bodies, and the Dartmouth 
compliance and quality assurance groups of all study related documents (e.g., source 
documents, regulatory documents, data collection instruments, study data.). The 
investigator will ensure the capability for inspections of applicable study-related facilities 
(e.g., diagnostic laboratory). 
 
RECORD RETENTION 
Following closure of the study, the investigator will maintain all site study records in a safe 
and secure location. The records are maintained to allow easy and timely retrieval when 
needed (e.g., audit or inspection) and, whenever feasible, to allow any subsequent review 
of data in conjunction with assessment of the facility, supporting systems, and staff. Upon 
completion of study analysis, research information is stored in a password protected, 
secure research server behind the firewall at the WRJ VA indefinitely or at Dartmouth 
College Records Management off-site storage located at 6218 Etna Road, Hanover, NH. 
Documents are shredded on site after 50 years of storage. 
Electronic case report forms, participant, and study information will be kept in the Velos 
eResearch password-protected database (or equivalent) indefinitely. 
 

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SAFETY AND DATA MONITORING 
This study will be monitored by the Data Safety Monitoring and Accrual Committee 
(DSMAC) of the Norris Cotton Cancer Center. The Committee meets quarterly to review 
accrual rates and information for studies that have accrued participants. The Clinical 
Cancer Review Committee (CCRC) determines the frequency of DSMAC review.  The 
DSMAC has the authority to suspend or to recommend termination to the CCRC of all 
research activities that fall within its jurisdiction. In the event that a study is suspended or 
terminated, that information will be forwarded to the CPHS (Dartmouth IRB) office. 
 
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