High-Flow Oxygen for Exertional Dyspnea in Cancer Patients
Phase: PHASE2
Conditions: Dyspnea, Malignant Neoplasm
Sponsor: M.D. Anderson Cancer Center

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High-Flow Oxygen for Exertional Dyspnea in Cancer Patients 
 
Principal Investigator: Dr. David Hui 
 
Co-Investigators: Dr. Eduardo Bruera, Dr. Karen Basen-Engquist, Dr. Donald Mahler, 
Dr. Anne Tsao, Dr. George Eapen, Dr. Juan Lopez-Mattei, Dr. Steven Lin, 
Dr. Melenda Jeter, Dr. Daniel Gomez, Dr. Charles Lu, Dr. Frank Fossella, 
Dr. Saadia Faiz, Dr. Lara Bashoura 
 
Biostatistics: Dr. Kenneth Hess 

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Funding source: This study is supported by a Mentored Research Scholar Grant in 
Applied and Clinical Research, MRSG-14-148-01-CCE from the American Cancer 
Society (P.I. David Hui). The funding for this study starts January 1, 2015. 
 
A. STUDY OBJECTIVES 
A.1. Primary Objective. Obtain preliminary estimates of the effect size of oxygen and 
high flow rate on exertional dyspnea (modified Borg Scale adjusted for work rate and 
baseline dyspnea). Our working hypothesis is that a high flow rate and oxygen will be 
associated with lower levels of exertional dyspnea than will the control during structured 
exercise sessions in cancer patients. 
 
A.2. Secondary Objective #1. Determine the completion rate of a randomized 
controlled trial of exertional dyspnea in cancer patients. Our working hypothesis is  that 
at least 80% of patients will participate in the structured exercise sessions until they 
experience volitional fatigue and complete all dyspnea study assessments. 
 
A.3. Secondary Objective #2. Obtain preliminary estimates of the effects of oxygen 
and flow rate on physiologic function (respiratory rate and oxygen saturation) and 
exercise capacity (work rate and exercise duration). Our working hypothesis is that 
oxygen and high flow rate will improve physiologic function and exercise capacity. 
 
B. BACKGROUND AND SIGNIFICANCE 
B.1. Dyspnea is defined as “a 
subjective experience of breathing 
discomfort 
that 
consists 
of 
qualitatively distinct sensations that 
vary in intensity.”(Parshall et al. 
2012) It occurs in approximately 
10%-70% of cancer patients and is 
one of the most feared symptoms 
(Solano et al. 2006, Tishelman et al. 
2007). More than 80% of patients 
with dyspnea have breakthrough 
episodes, particularly with physical 
exertion (Reddy et 
al. 2009). 
Dyspnea 
is 
associated 
with 
decreased function, quality of life, 
and survival (Maltoni et al. 2005). 
The pathophysiological features of 
dyspnea are shown in Figure 1. The 
sensory cortex receives afferent 
input from various peripheral and 
central stimuli, 

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generating the sensation of breathlessness (Mahler 2011, Parshall et al. 2012). 
Parenchymal metastasis, lymphangitic carcinomatosis, airway obstruction, pleural 
effusion, pneumonia, pulmonary embolism, and atelectasis may cause difficulty breathing 
in the context of progressive cancer. 
The current management of dyspnea involves treating any reversible causes and 
providing supportive measures. Systemic opioids are effective for dyspnea relief 
(Jennings et al. 2002). Low-flow supplemental oxygen (up to 5 L/min) has also been 
found to be effective, but only in patients with hypoxemia (Bruera et al. 1993, Cranston 
et al. 2008). The current method of supplemental oxygen delivery using nasal prongs 
and non-re-breather masks is limited because these modalities can only deliver limited 
oxygen flow and are uncomfortable. These impracticalities, coupled with their lack of 
effectiveness at relieving dyspnea in non-hypoxemic cancer patients, indicate a need for 
more effective oxygen delivery methods for dyspnea (Ben-Aharon et al. 2008, Viola et al. 
2008). The proposed research is expected to provide new insights into the therapeutic 
role of HFOx for exertional dyspnea. 
B.2. High-flow oxygen is an innovative heat and humidification device that can deliver 
oxygen at a rate of up to 40 L/min via nasal prongs. The device is postulated to relieve 
dyspnea by maintaining a level of PaO2 superior to that of LFOx, which may decrease 
and inhibit the activation of dyspnea chemoreceptors (Figure 1). The high-flow 
mechanism, whether delivering oxygen or air, may also improve ventilation (Dewan and 
Bell 1994), augment end-distending pressure (Locke et al. 1993), reduce nasopharyngeal 
inspiratory resistance (Dysart et al. 2009), and stimulate the trigeminal and 
glossopharyngeal nerves (Figure 1). The inhalation of heated and humidified gas may 
also decrease bronchoconstriction, improve airway conductance (Fontanari et al. 1997), 
and reduce the metabolic cost of gas conditioning (Dysart et al. 2009). Because of these 
novel mechanisms, we hypothesize that HFOx and HFAir will relieve  dyspnea in patients 
who are not included in the traditional target population (i.e., patients with hypoxemia), 
including those with normal oxygen saturation. This non-hypoxemic population makes 
up a large proportion of cancer patients with dyspnea (Hui et al. 2013b). To our 
knowledge, to date, no study has specifically evaluated HFOx for dyspnea in non-
hypoxemic cancer 
patients, nor has anyone studied 
the therapeutic role of HFAir in any 
patient population. 
B.3. 
High-flow 
supplemental 
oxygen improved dyspnea in 
hypoxemic cancer patients (Hui 
et 
al. 
2013a). We 
recently 
conducted the first 
randomized 
controlled trial comparing HFOx 
and 
bilevel 
positive 
airway 
pressure (two hours each) in 
advanced cancer patients 
with 
refractory dyspnea. Twenty-four of 
30 (80%) patients completed the 
study    interventions,    suggesting 

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that a study of these two devices is feasible in this patient population. HFOx (mean 
change, 1.9; 95% CI, 0.4-3.4; P=0.02) was associated with significant improvements in 
dyspnea (Figure 2). Remarkably, two patients who completed HFOx reported low 
dyspnea scores (≤2 of 10) up to 1 hour after discontinuing use of the devices. This 
observation is of particular interest because the mechanical effect of HFOx on breathing 
effort may have a long-lasting effect on dyspnea. Overall, 10 of 13 (77%) patients who 
completed HFOx reported dyspnea improvement, with none experiencing significant 
adverse effects. Of note, this study was conducted in patients who were predominantly 
hypoxemic (93%) and did not respond to LFOx. These data support the feasibility of 
conducting a clinical trial with HFOx in cancer patients and provide preliminary evidence 
of its efficacy. Importantly, HFOx and HFAir have not been formally tested in non- 
hypoxemic patients, which is why the proposed trial is particularly novel. 
B.4. Low-flow supplemental oxygen for non-hypoxemic cancer patients (Bruera et 
al. 2003). In a double-blind, randomized trial, we found that LFOx at 5 L/min did not 
improve dyspnea during a 6-minute walk compared with LFAir at 5 L/min. The results of 
this important study highlight the lack of efficacy of LFOx for exertional dyspnea in non- 
hypoxemic patients and the need to evaluate novel treatment options (i.e., HFOx and 
HFAir). 
B.5. Study rationale. We expect to advance our understanding of how HFOx can be 
used to treat exertional dyspnea in non-hypoxemic cancer patients. The effective 
management of dyspnea may ultimately help alleviate this devastating symptom. By 
elegantly dissecting the high-flow mechanism from the oxygen content and capturing 
changes in physiologic parameters, we will gain a better understanding of the 
mechanisms that help alleviate dyspnea and devise newer, more effective treatments. 
This contribution will be significant because it represents a key step in a  continuum 
of research that is expected to lead to the optimization of HFOx delivery  and thus relieve 
exertional dyspnea in cancer patients and improve their quality of life. In the current 
proposed study, HFOx, HFAir, LFOx, and LFAir will be administered 
during 
cardiopulmonary   exercise   testing.   If   the 
preliminary results of this randomized phase 
II study demonstrate that oxygen or high flow 
rate affect dyspnea intensity, the next step will 
be to conduct a larger multi-institutional, 
randomized controlled trial that is adequately 
powered to compare HFOx with a control 
intervention, particularly in the home setting. 
This would be a logical extension of the 
proposed study because the use of HFOx has 
predominantly been limited to the hospital 
setting. The technology that allows this device 
to be used at home in an affordable manner 
is just now becoming available (i.e., Flowrest 
device). Once 
the efficacy of HFOx is 
confirmed, patients will have much more 
access to this therapeutic measure.   The   
proposed   study   has   the 

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potential to greatly improve patients’ symptom burden, function, and quality of life. 
 
C. RESEARCH DESIGN AND METHODS 
C.1. Overall study design (Figure 3). This is a 2x2-factorial, double-blind, randomized, 
controlled trial of HFOx, HFAir, LFOx, and LFAir in non-hypoxemic cancer patients with 
dyspnea. We plan to enroll 50 patients in total. Enrolled patients will first complete a 
baseline structured exercise session with LFAir and return 3±2 days later to  be randomly 
assigned to receive one of the four study interventions during the second structured 
exercise session. We will use a computer-generated sequence in permuted blocks for 
randomization, stratified by baseline dyspnea modified Borg Scale and work rate. Even 
with 2 different flow rates, patients and research staff will be blinded to the gas (i.e., 
oxygen v. air); thus, this will remain a double-blind study. On the basis of our experience 
conducting symptom control trials, we believe this study design is feasible and will not 
be an undue burden for patients. The rationale for the current study design is as follows: 
• Factorial design—This will allow us to examine the oxygen and high flow effects 
separately while providing preliminary data about synergism between oxygen and 
flow. 
• Parallel design—This design will minimize study burden and attrition compared with 
a crossover study that requires 5 exercise sessions. We will adjust for inter- individual 
differences by accounting for both baseline dyspnea score and maximal work rate. 
• Baseline exercise sessions on day 1—Patients will first complete an incremental 
exercise test to familiarize themselves with the cycle ergometer and to identify their 
maximal work rate. They will then complete a structured exercise session with cycle 
ergometry at a constant work rate of 80% peak with LFAir, which will inform us of 
their dyspnea response and isotime. 
• Use of LFAir at baseline test—Neither LFAir nor LFOx has been found to improve 
dyspnea in non-hypoxemic patients. This will address the placebo effect with nasal 
cannula use. 
• Inclusion of HFOx and HFAir arms—To our knowledge, HFOx has not been tested 
in non-hypoxemic cancer patients. No study has examined the therapeutic role of 
HFAir in any patient population. 
• Inclusion of LFOx arm—Although LFOx was found to be ineffective compared with 
LFAir during the 6-minute walk test, its utility has not been tested with cycle ergometry 
in cancer patients. 
• Stratification—To minimize the possibility that baseline dyspnea and exercise 
performance will affect the outcome, we will stratify patients by this  baseline dyspnea 
modified Borg Scale score at rest (0-3/10 vs. 4-7/10; >7/10 will be excluded) and by 
their work rate during the first structured exercise session (≤50 W vs. >50 W). The 
objective of stratified randomization is to ensure a balance of the treatment groups 
with respect to the various combinations of predictive variables (i.e., the baseline 
Borg scale and work rate). This will ensure that a similar number of patients from each 
strata are randomly assigned to each treatment arm but will not require a similar 
number of patients in each strata. Thus, stratification should not affect the 
enrollment rate. 

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C.2. Eligibility criteria. The eligibility criteria are shown in Table 1. The rationale for 
including patients with obstructive and restrictive lung disease in this study is that the 
mechanisms of dyspnea relief (e.g., trigeminal nerve stimulation and decreased 
breathing effort; see Figure 1) are applicable to both types of pulmonary disorder. To 
ensure homogeneity in the study population and patient safety, we will exclude patients 
with severe obstructive airway disease (FEV1/FVC <70% post bronchodilator  and forced 
expiratory volume in 1 second <30% predicted). 
  Table 1. Study Eligibility Criteria  
 
Inclusion Criteria 
1. Diagnosis of cancer, with evidence of primary or secondary 
lung involvement 
2. Average dyspnea Borg Scale ≥4 of 10 with severe exertion 
over the past week 
3. Oxygen 
saturation >90% on ambient air at time of 
assessment 
4. Able to communicate in English or Spanish 
5. Karnofsky performance status ≥50% 
6. Age ≥18 years 
7. Seen at Supportive Care, cardiopulmonary center, thoracic 
radiation oncology or thoracic medical oncology 
Exclusion Criteria 
1. Resting dyspnea modified Borg Scale >7 of 10 at enrollment 
2. Severe obstructive lung disease (FEV1/FVC <70% post 
bronchodilator and forced expiratory volume in 1 second 
<30% predicted ) 
3. Delirium (i.e., Memorial delirium rating scale >13) 
4. History of unstable angina or myocardial infarction in the last 
week 
5. Acute pulmonary embolus or pulmonary infarction in the last 
week 
6. Thrombosis of lower extremities in the last week 
7. Acute  myocarditis,  pericarditis,  or endocarditis 
in the last 
week 
8. Symptomatic aortic stenosis or syncope in the last week 
9. Suspected dissecting aneurysm 
10. Severe untreated resting arterial hypertension (>200 mmHg 
systolic, >120 mmHg diastolic) at the time of enrollment 
11. Uncontrolled 
arrhythmias 
causing 
symptoms 
or 
hemodynamic compromise in the last week 
12. Uncontrolled heart failure in the last week 
13. Pleural effusion requiring thoracentesis within 1 week of 
study enrollment or scheduled during the study period 
14. Airway obstruction requiring stenting within 1 week of study 
enrollment or scheduled during the study period 
15. Pneumonia 
requiring antibiotics at the time of study 
enrollment 
C.3. 
Screening 
and 
recruitment. 
Patients 
attending our supportive 
care, thoracic oncology, 
or 
cardiopulmonary 
outpatient clinics will be 
screened for this  study. 
A 
two-step 
consent 
process will be 
used. 
First, verbal consent will 
be obtained by the study 
staff before 
screening 
potential participants to 
determine their eligibility. 
Outpatients 
may 
be 
contacted 
by 
phone 
within 1 week prior to 
their scheduled 
clinic 
visit to inform them of the 
study so that they can 
make 
the 
necessary 
arrangements 
 
to 
participate. 
Eligible 
patients will be formally 
enrolled in the  study after 
they have 
signed the 
informed consent form 
indicating 
their 
willingness to participate 
in 
the 
trial. 
Once 
enrolled, the 
research 
staff will work with the 
patient to identify the 2 
ideal study days. We will 
document the number of 
patients 
who 
are 
screened, 
approached, 
eligible, enrolled, and 
randomized  for  the  study  and  the  number  who  complete  it.  Patients’ reasons for 

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declining to participate will also be captured. 
Our clinic has 3 physicians who are supported  by a  fully staffed interdisciplinary team 
and who see a mean of 30 patients (8-10 new consults) per day, 5 days per week. One 
of the physicians is embedded in the thoracic medical oncology clinic and routinely 
receives referrals for dyspnea. 
We will document recruitment and retention rates and reasons that patients dropout. 
We expect that at least 80% of patients will participate in the structured exercise sessions 
until they experience volitional fatigue and complete all dyspnea study assessments. 
Because patients have to make 2 extra visits to MD Anderson for study assessment, 
we will provide an honorarium of $50 gift card/study day for a total of $100 over 2 study 
days. We will also provide patients a parking voucher at each study visit as 
reimbursement for their parking costs (up to 2 vouchers total). 
C.4. Randomization. Patient randomization will be performed using the Clinical Trial 
Conduct website (https://biostatistics.mdanderson.org/ClinicalTrialConduct), which is 
maintained by the Department of Biostatistics at MD Anderson. The trial statistician will 
train the respiratory therapists in the use of this website for randomizing patients. We 
will use a computer-generated sequence in permuted blocks to randomize patients, in a 
1:1 ratio, to the two treatment interventions (high flow vs. low flow and oxygen vs. air). 
To minimize the possibility that baseline dyspnea and exercise performance will affect 
the outcome, we will stratify patients by baseline dyspnea modified Borg Scale score at 
rest (0-3/10 vs. 4-7/10) and by work rate during the first structured exercise  session (≤50 
W vs. >50 W). 
C.5. Study interventions. Highly trained respiratory therapists will use the Optiflow 
Respiratory Humidifier (Fisher & Paykel Healthcare, Inc, Irvine, CA, USA) to deliver 
HFOx. This device was approved by the U.S. Food and Drug Administration in 2007 
(K033710) to add “moisture to, and to warm, the breathing gases for administration to a 
patient. Gases available for medical use do not contain sufficient moisture and may 
damage or irritate the respiratory tract, or desiccate secretions of patients whose 
supraglottic airways have been bypassed. This may be indicated for patients requiring 
mechanical ventilation, positive pressure breathing assistance, or general medical 
gases”. HFOx will be delivered via nasal prongs. The flow of oxygen will be maximized 
(set between 20 and 60 L/min), if tolerated, to minimize dyspnea. The FiO2 will be set at 
100%. The level of heat (between 35° and 37°) will be adjusted to keep the patient 
comfortable. HFAir will also be delivered by Optiflow in an identical manner to HFOx, 
except that we will use pressurized air instead of oxygen. LFOx and LFAir will be 
provided at 2 L/min using a nasal cannula identical to that used for high-flow devices. 
This flow rate is based on the results of a previous large randomized controlled trial of 
oxygen use in non-hypoxemic patients (Abernethy et al. 2010). A respiratory care 
specialist will be present throughout the study period. We have previously collaborated 
with the same team of respiratory care specialists on other research projects on high- 
flow oxygen delivery. 
C.6. Blinding procedure. The patients, research staff, and exercise physiologist will be 
blinded to the assignment of the gas (i.e., oxygen vs. air). Only the respiratory therapist 
administering the gas will be aware of its identity. Optiflow requires both an air tank and 
oxygen tank, with a 50-psi outlet. To ensure proper blinding, the respiratory therapist will 
set up the gas delivery device before the patient and staff enter the room. The gas tanks 

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and device settings will be covered. The respiratory care specialist will be specifically 
asked to not to discuss the identity of the study gas. We will assess blinding by asking 
the patients and study staff about the identity of the gas at the end of study. The flow 
rate cannot be blinded in this study. 
C.7. Exercise ergometry will be conducted by a trained PROSPR exercise physiologist 
in accordance with the 2003 American Thoracic Society and American College of Chest 
Physicians guidelines (2003). We chose to use cycle ergometry instead of other 
modalities (e.g., a 6-minute walk test) to induce exertional dyspnea because  a stationary 
bicycle makes it easier for us to deliver oxygen, monitor the physiologic parameters 
and work rate, and minimize falls. On the first day, we will administer the baseline 
questionnaires, including demographics, medication history, performance status, 
Edmonton Symptom Assessment Scale, dyspnea survey, cancer dyspnea scale, and 
dyspnea modified Borg scale. We will also measure patients’ height, weight, resting ECG, 
resting blood pressure, and resting heart rate. 
Before the start of exercise, research staff will explain the exercise test sequence to 
the participants, including how to use the dyspnea modified Borg scale. The patient will 
be asked to pedal at a cadence of approximately 60 rpm during the test. The metabolic 
cart (Parvo True One, Sandy, UT) will be used to monitor cadence, measure work rate 
during the exercise test, and control resistance on the cycle ergometer. Patients will 
begin by pedaling with no resistance for 60 seconds, followed by a warm-up stage of 
120 seconds, pedaling at 10 watts (W) of resistance for the first minute and 20 W for the 
second minute. Their blood pressure and heart rate will be recorded every 2 minutes. 
Oxygen saturation and electrocardiography results will be monitored every 2 minutes 
during the exercise sessions. The dyspnea modified Borg Scale will also recorded every 
minute. Patients will perform cycle ergometry tests at an increment of 10 W/min without 
oxygen until they experience volitional fatigue. During the 3-minute recovery stage at 10 
W, their blood pressure, heart rate, and dyspnea modified Borg scale (rating of perceived 
dyspnea scale, RPD) will be recorded every minute. 
After at least a 2-hour rest period, patients will perform a structured  exercise session, 
with an initial warm up period of ≤3 minutes followed by constant work rate cycle 
ergometry at 80% of the peak work rate and using LFAir, until they experience volitional 
fatigue. The work rate during this test will be used for stratification. 
During the second session, 3±2 days later, patients will be asked to repeat the 
structured exercise with one of the four study interventions. The study assessments 
conducted on the first day will be repeated. We will use the constant work rate test for 
the comparison because it has been found to be more responsive for dyspnea than 
have incremental tests (Teunissen et al. 2007). A gas exchange analysis will not be 
conducted because the high flow and oxygen content can interfere with measurements 
of VO2 (ml/kg/min), VO2 (L), VCO2 (L), VE (L), PetO2 (mm Hg), and PetCO2 (mm Hg), 
making accurate assessments infeasible. After consulting with our pulmonary 
collaborator and exercise physiology team (PROSPR), we have decided to measure the 
work rate and use this as a factor for stratification. 
Although we do not expect patients to experience desaturation during exercise based 
on our previous studies, if we find significant hypoxemia during testing with LFAir or HFAir 
(and even LFOx and HFOx) arms, patients will not be able to continue with this study  
and  will  be  considered  as  dropouts.  The  termination  point  is  defined  by (1) 

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participant volitional fatigue, (2) abnormal hemodynamic responses to increasing 
workload, (3) inability to maintain bike cadence, (4) arrhythmias detected on the ECG 
including changes suggesting ischemia, (5) loss of any monitoring signals, or (6) 
hypoxemia [O2 saturation <88%] while exercising. Patients will be  monitored throughout 
structured exercise testing, and will have access to urgent medical care if needed. 
Because this study is designed to induce dyspnea with exercise and some participants 
had to stop the exercise testing due to leg cramps before they became dyspneic, we 
will ask study participants not to continue with the rest of the study if their maximum level 
of dyspnea Borg scale intensity is less than 4/10 by the end of the first incremental test 
(in keeping with inclusion criteria #2). We will enroll a total of 50 patients who completed 
all 3 exercise tests and had dyspnea of at least 4/10 at the end of the first incremental 
test. 
 
C.8. Study assessments. See Table 2 for a detailed description of the study 
assessments. The dyspnea Borg scale (intensity) will be the primary endpoint  because 
it has been used in multiple other cycle ergometry-based studies (Mahler et al. 2005, 
Mahler et al. 2007, Mahler et al. 2009, Travers et al. 2008). This is a 0 to 10 categorical 
scale for rating the severity of dyspnea by the patient, and is the primary outcome 
measure in this study. It is a ratio scale with descriptive anchors throughout the range in 
which a rating of 8 signifies breathlessness twice as severe as 4, which in turn is twice as 
severe as 2 (Laboratories 2002). We will be measuring it at baseline and then every 
minute during the structured exercise tests. This scale has been used extensively in 
pulmonary research and has good reliability and validity for assessing  dyspnea (Dorman 
et al. 2007, Kendrick et al. 2000, Mancini and Body 1999). The minimal clinically important 
difference is 1.0 in patients with chronic obstructive pulmonary disease (Ries 2005). This 
scale can be administered quickly, and was found to be easy to use by patients (Kendrick 
et al. 2000). In a study that compared the dyspnea modified Borg Scale, numeric rating 
scale and visual analog scale, the modified Borg scale was preferred by participants and 
was recommended as the best tool to quantify dyspnea intensity (Hareendran et al. 
2012). Furthermore, its use is recommended by the American Thoracic Society and 
American College of Chest Physicians for Cardiopulmonary Exercise Testing (ATS/ACCP 
2003). The modified  dyspnea Borg scale is also routinely used by our PROSPR group 
that conducts the cycle ergometry testing. We will also assess the degree of 
unpleasantness associated with dyspnea using a separate modified Borg scale as well. 

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Table 2. Summary of Study Assessments  
Warm 
 
First 
 
Second 
up 
structured test    structured test 
Assessment (estimated time to complete) 
Before    During  Before  During 
 
Baseline demographics (15-20 min)1 
 
Medication history (5 min)2 
 
 
 
 
 
Karnofsky performance status (1 min)3 
 
 
 
 
Edmonton Symptom Assessment Scale (5 min)4 
 
Dyspnea survey (5 min)5 
 
Cancer Dyspnea Scale (5 min)6 
 
 
Baseline Dyspnea Index (5 min)7 
 
Modified Dyspnea Borg scale – intensity and 
unpleasantness (<1 min)8 
 
 
 
 
Vital signs, electrocardiogram (3 min)9 
 
 
 
 
Exercise test variables10 
 
 
 
Oxygen device settings11 
 
 
Adverse effects (5 min)12 
 
 
 
 
Blinding, 
global 
impression, 
satisfaction 
(<3 
min)13 
End 
 
1 Medical record number, birthdate, sex, race, cancer diagnosis, co-morbidities, dyspnea cause, 
spirometry, and baseline electrocardiogram. Bedside spirometry will be performed at baseline 
using the MicroLoop spirometer (Micro Direct, Inc., Lewiston, ME) according to published 
guidelines (Miller et al. 2005). This device was approved by the American Thoracic Society and 
US FDA. Various spirometry parameters will be documented, including vital capacity, forced 
expiratory volume in 1 second, forced vital capacity, forced expiratory volume//forced vital 
capacity, peak inspiratory flow, and peak expiratory flow. We will also assess maximal inspiratory 
pressure using the NS 120-TRR NIF Monitor (Instrumentation Industries Inc., Bethel Park, PA) 
according the American Thoracic Society Guideline.(2002) 
2 The frequency of use of scheduled and as-needed opioids, steroids, and bronchodilators in the 
4 hours before and during the study. 
3 An 11-point scale that rates patients’ functional status between 0% (death) and 100% 
(completely asymptomatic) (Schag et al. 1984). 
4 Validated questionnaire that measures 10 symptoms (pain, fatigue, nausea, depression, anxiety, 
drowsiness, shortness of breath, appetite, sleep, and well-being) using numeric rating scales 
(Bruera et al. 1991). ESAS will be reported as part of patient characteristics because it provides 
useful information on a patients’ symptom expression/burden at baseline. These variables could 
potentially be predictors of symptom response. 
5 Characterization of patients’ level dyspnea, number of exacerbation episodes,  triggers, episode 
duration, and activity level 
6 Validated 12-item questionnaire to assess the quality of dyspnea in cancer patients during the 
previous few days (Tanaka et al. 2000). Each item has a score between 1 and 5, for a maximum 
of 60. 
7 The Baseline dyspnea index (BDI) is a validated scale used to assess dyspnea under 3 domains: 
1) functional impairment, which examines the impact that dyspnea has on the ability to carry out 
daily activities; 2) magnitude of task, which examines the type of task that results in dyspnea; 
and 3) magnitude of effort, which establishes the level of effort that leads to dyspnea. BDI ranges 
from 0 (very severe impairment) to 4 (noimpairment) for each domain, with a total score of 0 to 
12.(Mahler et al. 1984, Mahler and Wells 1988, Witek and Mahler 2003) 
8 The Modified Dyspnea Borg Scale-Intensity is the primary outcome measure, a 0 (no dyspnea) 
to 10 (worst dyspnea) ratio scale validated for rating dyspnea severity (Dorman et al. 2007, 

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Powers and Bennett 1999); this will be measured every minute during  exercise  testing. Modified 
Dyspnea Borg Scale-Unpleasantness is one of the secondary outcomes. 
9 Heart rate, respiratory rate and blood pressure will be measured at baseline and every 2 
minutes during the exercise sessions. Continuous oxygen saturation and electrocardiogram 
monitoring will be provided during the exercise sessions, and documented every 2 minutes 
during testing.  During the cool down period, these will be measured every 1 minute 
10 Work rate (Watts) is calculated as follows: resistance of the flywheel x distance/revolution 
(m/revolution) x pedaling rate (revolution/min) x time (minute). One Watt is equivalent to 6 
kg⋅m⋅min-1. It will be measured continuously during exercise testing. We will also document 
symptoms (e.g. fatigue and leg discomfort) q2min during exercise testing, as well as reasons for 
stopping (e.g., breathlessness, fatigue, and leg discomfort) and the duration of exercise. 
11  Device settings include FiO2, oxygen flow, and temperature. 
12 Adverse effects related to supplemental oxygen use, such as dry eyes, dry nose, nasal 
moisture, and anxiety, will be assessed using a numeric rating scale from 0 (not at all) to 10 
(worst possible) before and after the intervention. 
13 We will assess blinding (oxygen v. air) and global impression (better/no change/worse) of 
patients and research staff. 
C.9. Exertional dyspnea clinical trials (Hui et al. 2014). Our department has an 
invested interest in developing novel therapeutics for exertional dyspnea in cancer 
patients. We have just completed a double-blind, randomized controlled trial to determine 
the effect of subcutaneous fentanyl on exertional dyspnea. After a baseline 6- minute walk 
test, patients were given fentanyl or a placebo and then asked to repeat the test. We 
enrolled 20 non-hypoxemic cancer patients in 5 months, with  100% completion. We also 
currently have 2 active double-blind, randomized controlled trials with fentanyl pectin 
nasal spray (expected to complete accrual by Feb 2015) and fentanyl buccal tablet. 
Because these opioid trials can only enroll patients who are opioid tolerant there 
should be many eligible patients for the proposed study. 
C.10. Co-interventions. We will ask patients to use their usual inhaled medications on 
the day of the test as appropriate. 
C.11. Training of research staff. An orientation will be held with all research staff 
involved in this study to introduce them to the study design and standardize the provision 
of each intervention. Particular attention will be paid to ensuring that research staff 
provide patients with proper instructions so they understand the study assessments. We 
will also have several mock-ups for practicing the study procedures. 
C.12. Data Safety Monitoring Board (DSMB). The MD Anderson DSMB will be 
providing monitoring for patient safety and data quality assurance purposes. 
 
D. STATISTICAL ANALYSIS 
D.1. Sample size justification. Using 10 patients per arm (assuming 20% attrition, 50 
total), we will have 86% power to detect a 1-standard deviation (SD) main effect and 
86% power to detect a 2-SD interaction effect (assessed as the difference between the 
joint effect and an additive effect) with an alpha of 5%. These are large effects, but the 
main objective is to obtain preliminary estimates of effect sizes. We have expressed the 
treatment effects as multiples of the standard deviation because we do not have valid 
preliminary estimates of the within-group standard deviations on which to base these 
calculations. 
D.2. Analysis plan. For the primary analysis, we will use a general linear model, with a 
Borg dyspnea score at isotime as the outcome variable and including the following 

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parameters as covariates: flow rate, oxygen, flow rate-oxygen interaction, work  rate, and 
baseline dyspnea at rest, prior to the first exercise test. Isotime is defined as the time 
of the last set of measurements before completion of the baseline constant work rate 
test. Because of HFOx, VO2 max cannot be accurately measured. Instead, we will 
calculate the work rate (in watts), defined as the resistance of the flywheel x 
distance/revolution (m/revolution) x pedaling rate (revolution/min) x time (minute). 
Because dyspnea is also repeatedly measured over time, secondary analyses will 
include a mixed-effects linear model on the longitudinal dyspnea scores, using the same 
5 model parameters. For all analyses, we will use data graphs and residual analyses to 
verify assumptions, with data transformations as necessary. If more than 10% of patients 
are missing data, we will use multiple imputation in our analyses. Recognizing that 
dyspnea in cancer patients may have multiple etiologies, we will document its 
potential causes and perform subgroup analyses to determine whether a particular patient 
group benefits more from the study interventions. These analyses will be considered 
exploratory and hypothesis-generating. If y is the endpoint, x1 is the flow rate (1 for 
high and 0 for low), and x2 is oxygen (1 for oxygen and 0 for ambient air), we will fit the 
following linear model: y = a + b1*x1 + b2*x2 + b3*x1*x2, with some additional terms. The 
effect of the flow rate (i.e., the adjusted mean difference between high and low flow) 
can be calculated as b1 for ambient air and b1 + b3 for oxygen. Similarly, the effect of 
oxygen can be calculated as b2 for low flow and b2 + b3 for high flow. Approximate 
95% confidence intervals for these effect estimates can be computed given the 
estimated covariance matrix of the model parameters. 
We will estimate the proportion of patients who complete the study; this analysis will 
include an appropriate 95% confidence interval. 
To estimate the effects of oxygen and flow rate on physiologic function (respiratory 
rate and oxygen saturation) and exercise capacity (work rate and exercise duration), we 
will use mixed-effects linear models because most of these are measured repeatedly over 
time. Given the limited number of patients, the results will be considered exploratory. 
Adverse events will be assessed using a numeric rating scale from 0 to 10 before and 
after intervention. Differences in these scores for each type of adverse event will be 
analyzed using general linear models, as described above for the primary endpoint. 

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E. DATA CONFIDENTIALITY PROCEDURES 
Health information will be protected and we will maintain the confidentiality of the data 
obtained from the patient's chart. 
Collection of identifiers: We will collect and securely store patients' identifiers 
(including name and medical record number). Each patient will be assigned a study 
number that will be the only identifier to figure in the analytical file and personal data will 
not be disclosed in any form. The key linking these numbers will be retained in a 
securely locked file by the investigator. 
Data Storage: Protection of electronic and paper records will be guaranteed. All 
electronic records will be stored on password-protected institution computers behind the 
institution firewall.  Any paper records will be classified and stored in locked files  inside 
a locked office. 
Training of personnel: Only MDACC personnel trained in maintaining confidentiality, 
the principal investigators and co-investigators, will have access to study records. 
Data sharing: Study data will not be shared with any individuals or entities without an 
IRB-approved protocol. The data will be kept by the principal investigator in a locked file 
cabinet and password protected computers. 
Final disposition of study records: PHI may be maintained indefinitely, aggregated in 
the future, and used for future IRB-approved research studies. 
 
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