High-Flow Oxygen for Dyspnea in Hospitalized Cancer Patients
Phase: PHASE2
Conditions: Cancer
Sponsor: M.D. Anderson Cancer Center

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High-Flow Oxygen for Dyspnea in Hospitalized Cancer Patients 
 
Principal Investigator: Dr. David Hui 
 
Co-Chair: Dr. Eduardo Bruera 
Collaborators: Dr. Dave Balachandran, Dr. Anne Tsao, Dr. Kenneth Hess, Dr. 
Ahmed Elsayem, Saji Thomas, RT,  
Lara Bashoura, MD, Saadia Faiz, MD, Sriram Yennu, MD 

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Funding source: This study is supported by the Sabin Family Fellowship Award (P.I. 
David Hui). The funding for this study starts March 1, 2016. 
 
A. STUDY OBJECTIVES 
A.1. Primary Objective. Obtain preliminary estimates of the effect size of high flow 
oxygen and air on dyspnea. Our working hypothesis is that high flow oxygen/air will be 
associated with lower levels of dyspnea than low flow oxygen/air in cancer patients. 
A2. Secondary Aim #1. Determine the completion rate of a randomized controlled trial 
of dyspnea in cancer patients. Our working hypothesis is that at least 80% of patients 
will complete the 4 periods of this study. 
A.3. Secondary Aim #2. Obtain preliminary estimates of the effects of high flow oxygen 
and air on physiologic function (oxygen saturation, respiratory rate, transcutaneous 
CO2). Our working hypothesis is that high flow oxygen and air will improve physiologic 
function. 
 
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” 
1. It occurs in 
approximately 10%-70% of cancer patients 
and is one of the most feared symptoms 2, 
3. More than 80% of patients with dyspnea 
have breakthrough episodes, particularly 
with physical exertion 
4. Dyspnea is 
associated with decreased function, quality 
of 
life, 
and 
survival 
5. 
The 
pathophysiological features of dyspnea are 
shown in Figure 1. The sensory cortex 
receives 
afferent 
input 
from 
various 
peripheral and central stimuli, generating 
the sensation of breathlessness 
1, 
6. 
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 7. Low- 
flow supplemental oxygen (up to 5 L/min) has also been found to be effective, but only 
in patients with hypoxemia 8, 9. 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 10,  11. The 

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proposed research is expected to provide new insights into the therapeutic role of HFOx 
for dyspnea. 
B.2. High-flow oxygen is an innovative heat and humidification device that can deliver 
oxygen at a rate of up to 60 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 12, augment 
end-distending pressure 13, reduce nasopharyngeal inspiratory resistance 14, and 
stimulate the trigeminal and glossopharyngeal nerves (Figure 1). The inhalation of 
heated and humidified gas may also decrease bronchoconstriction, improve airway 
conductance 15, and reduce the metabolic cost of gas conditioning 14. 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 16. To our 
knowledge, to date, no published 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 17. 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 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 18. 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 

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study highlight the lack of efficacy of LFOx for 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 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. 
 
C. RESEARCH DESIGN AND METHODS 
C.1. Study design. This is a double-blind, 4- 
intervention, 
4-period 
crossover 
randomized 
controlled trial of HFOx, HFAir, LFOx, and  LFAir 
in non-hypoxemic cancer patients (Figure 3). We 
plan to enroll 36 patients in total. The eligibility 
criteria are listed in Table 1. We will use a 
computer-generated sequence for randomization. 
Even with 2 different flow rates, patients and 
research staff will be blinded to the gas (i.e., 
oxygen v. air) while a separate respiratory 
therapist will provide the study intervention; thus, 
this will remain a double-blind study. On the basis 
of our experience conducting symptom control 
trials, we believe this study design will not be an 
undue 
burden 
for 
hospitalized 
patients 
(approximately 1-2 hours, including washout).19 
The rationale for the current study design is as 
follows: 
 Crossover design—This design allows intra-individual comparison,  
thus 
maximizing study power (144 tests in 36 patients) in addition to providing overall 
preference.20 We use the Latin square design to minimize the sequences needed. 
 Intervention duration—We will limit this intervention to only 10 minutes in this 
proof-of-concept study to minimize study burden and attrition, and to examine the 
effect of short intervention. We expect the effect of gas exchange to be rapid. 
Previous dyspnea studies with oxygen delivery have utilized similar durations 8. 
 Variable washout period—although the washout period is expected to be short 
(<10 min), it has not been defined. Thus, we will measure dyspnea on the Numeric 
Rating Scale starting after 10 minutes of each intervention every 5 minutes until 
patient returns to within 1 point of the baseline level of dyspnea (i.e. immediately 
prior to starting the first intervention) before we proceed to the next intervention. 
 Inclusion of HFOx, HFAir and LFAir arms—HFOx has not been tested in non- 
hypoxemic cancer patients. No published study has examined the therapeutic role of 
HFAir in any patient population. The efficacy of LFAir has not been studied in the 
hospitalized population 21. 
 Use of LFAir as control—LFAir at 2 L/min is a well-accepted control intervention in 
published studies. 

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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C.3. Recruitment. Patients seen by the supportive care team, thoracic oncology, 
pulmonary medicine, or emergency care will be screened for this study. The supportive 
care inpatient consultation team sees 80 patients (10-20 new consults) per day. 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. Before signing 
any consent document, a respiratory care therapist will allow patients a trial of high-flow 
oxygen/air to ensure tolerance of high flow. 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 ideal time to conduct the study. We will document the number of patients who 
are screened, approached, eligible, enrolled, and randomized for the study and the 
number who complete it. When patients complete study procedures, they will be 
compensated with a $25 gift card as a show of appreciation for their time and 
participation. Patients’ reasons for declining to participate will also be captured. 
C.4. Randomization. Randomization will be performed immediately before the patient 
is ready to start study procedures by our study respiratory therapist 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 1:1:1:1 ratio, to the four treatment sequences from a Latin square. Each sequence 
has a specific order of high flow oxygen, low flow oxygen, high flow air, and low flow air. 
C.5. Study interventions. Respiratory therapists will use a high flow oxygen device 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 
Table 1. Study Eligibility Criteria 
Inclusion Criteria 
1. Diagnosis of cancer 
2. Patients seen by palliative care, thoracic oncology, pulmonary medicine, or emergency 
care at MD Anderson Cancer Center 
3. 
Dyspnea Numeric Rating Scale at rest ≥3 of 10 (average over last 24 hour) 
4. Non-hypoxemic (i.e. oxygen saturation >90% on ambient air) 
5. Able to communicate in English or Spanish 
6. Age ≥18 years 
7. Able to tolerate high-flow oxygen/air 
Exclusion Criteria 
1. Memorial Delirium Rating Scale >13 
2. Hemodynamic instability 
3. Respiratory failure requiring mechanical ventilation or non-invasive ventilation 
4. Frequent use of rescue opioids >8x/day or rescue bronchodilators >8x/day over last 24 
hours 
5. Currently requiring high flow oxygen for oxygenation 

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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 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. This flow rate is based on the results of a 
previous large randomized controlled trial of oxygen use in non-hypoxemic patients 21. 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. The patients and research staff will be blinded to the assignment of the 
gas (i.e., oxygen vs. air). The gas will be delivered via gas outlets inside the patient’s 
room, located behind the bed. Only the respiratory therapist administering the gas will 
be aware of its identity. To ensure proper blinding, the research staff will step out of the 
room while the respiratory therapist sets up the gas delivery device. The gas supply will 
be covered with a piece of cloth to ensure proper concealment. 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. Study outcomes. See Table 2 for a detailed description of the study assessments. 
We will also collect data on patient demographics and study feasibility outcomes (rates 
of enrollment and attrition). The study interventions will be provided to patients while at 
rest, and dyspnea ratings will only be assessed when patients are at rest. 
C.8. Co-interventions. We expect that co-interventions will be minimal because of the 
short study period. We will document any regularly scheduled,  bronchodilators or 
opioids given 1 hour before or during the study period. However, if patients required as 
need opioids (for pain or any other reasons) or bronchodilators during the study period, 
they will need to come off study and will need to be replaced. 
C.9. 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.10. Data Safety Monitoring Board (DSMB). The MD Anderson DSMB will be 
providing monitoring for patient safety and data quality assurance purposes. 
C.11. Dropouts. Patients will come off study if (1) they decide for any reason to stop; 
(2) they did not achieve within 1 point of the baseline level of dyspnea after 1 hour 
during the washout period, (3) they require as need opioids (for pain or any other 
reasons) or bronchodilators during the study period. These individuals will need to be 
replaced. 
C.12. Stopping rule. This is a short study and we expect limited attrition. We will stop 
the study at patient request or if patients required as need opioids (for pain or any other 
reasons) or bronchodilators during the study period. 

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Table 2. Summary of Study Assessments 
Baseline 
Intervention 
Washout 
period 
End of study 
Demographics and baseline data1 

- 
- 
- 
Dyspnea numeric rating scale (<1 min)2 

0, 5, 10 min 
q5min 
- 
Dyspnea Borg scale – intensity and 
unpleasantness (<1 min)3 

0, 5, 10 min 
q5min 
- 
Physiologic variables (5 min)4 

0, 10 min 
- 
- 
Blood pressure 

- 
- 

Adverse effects (<1 min)5 
- 
0, 10 min 
- 
- 
Length of washout (5+ min)6 
- 
- 

- 
Device settings7 


- 
- 
Blinding, preference (<1 min)8 
- 
- 
- 

1 We will collect birthdate, sex, race, cancer diagnosis, co-morbidities, dyspnea cause and 
baseline, Karnofsky Performance status, the frequency of use of scheduled and as-needed 
opioids, steroids, and bronchodilators in the 24 hours before and during the study. Validated 
questionnaires that will be assessed at baseline include the Edmonton Symptom Assessment 
Scale (measures 10 symptoms [pain, fatigue, nausea, depression, anxiety, drowsiness, 
shortness of breath, appetite, sleep, and well-being] using numeric rating scales 22) and the 
Cancer Dyspnea Scale (12-item questionnaire to assess the quality of dyspnea in cancer 
patients during the previous few days 23. Each item has a score between 1 and 5, for a 
maximum of 60). 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, 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 24. 
2 Dyspnea intensity assessed by Numeric Rating Scale is the primary measure. It is a 0 (no 
dyspnea) to 10 (worst dyspnea) categorical scale validated for rating the severity of dyspnea25- 
27. 
3 The intensity of and unpleasantness associated with dyspnea will be assessed using the 
Borg scale, a validated ratio scale that ranges from 0 (no dyspnea) to 10 (worst dyspnea).25, 27 
4 Heart rate, respiratory rate, oxygen saturation, and transcutaneous CO2 level will be 
measured. 
5 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). 
6 Dyspnea intensity will be assessed using the NRS scale every 5 minutes until patients return 
to baseline. The duration of washout is a useful secondary outcome. 
7  FiO2, flow rate, and temperature. 
8  We will assess blinding (oxygen v. air) of patients and research staff after each treatment. At 
  the end of the study, patients will be asked which of the 4 interventions they prefer  
 

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D. STATISTICAL CONSIDERATIONS 
D.1. Analysis plan. 
Design: We propose a 4-period, 4-intervention balanced Latin-square cross-over 
(Williams) design with 4 sequences and 36 patients (i.e., 9 replicates per sequence). 
The primary outcome is the Dyspnea Numeric Rating Scale (0-10). Each intervention is 
10-minutes long with NRS assessments at 0, 5 and 10 minutes. Washout periods 
between interventions will continue until NRS assessment returns to within one unit of 
baseline. 
Primary analysis: We will fit a mixed effects linear model to the Dyspnea Numeric 
Rating Scale data to account for the repeated measurements (i.e. 0, 5 and 10 minutes) 
which yield period, sequence, and carryover effects and to model the various inter- 
patient and intra-patient sources of variation. Appropriate data visualization and residual 
analyses will also be performed. The primary objective of the study is to obtain 
preliminary estimates of the effect sizes (In a mixed model, the slope of change will 
provide an estimate of effect size. We will also determine the mean change in NRS over 
10 minutes for each study intervention). 
Secondary analysis #1: We will estimate the completion rate as the proportion of 
patients starting treatment that complete all four interventions. 
Additional secondary analyses: Using mixed effects linear models we will obtain 
preliminary estimates of the study effects for physiologic function (oxygen saturation, 
respiratory rate, transcutaneous CO2). We will also assess washout period duration in a 
similar fashion. Finally, we will tabulate patient intervention preferences obtained at the 
end of the study. 
D.2. Sample size justification. We will enroll 36 patients over 2 years. Although due to 
the complexity of the statistical models we cannot accurately estimate the precision of 
our effect estimates, based on our experience with mixed effects models, 36 patients 
with 12 repeated measurements (3 times for each of 4 interventions) will provide 
adequate precision. If the completion rate is 80% then with 36 patients, a 95% 
confidence interval on this estimate would extend from 64% to 92%. 
 
E. DATA CONFIDENTIALITY PROCEDURES 
Study data will be collected and managed using REDCap (Research Electronic Data 
Capture) tools hosted at MD Anderson or hardcopy surveys. Participants will have the 
option to complete surveys electronically or hardcopy. Data entry of  any hardcopy 
survey will be completed using REDCap software.  REDCap  (www.project-redcap.org) 
is a secure, web-based application with controlled access designed to support data 
capture for research studies, providing: 1) an intuitive interface for validated data  entry; 
2) audit trails for tracking data manipulation and export procedures; 3) automated export 
procedures for seamless downloads to common statistical packages; and 4) procedures 
for importing data from external sources. In the case of multi-center studies REDCap 
uses Data Access Groups (DAGs) to ensure that personnel at each institution are 
blinded to the data from other institutions. REDCap (https://redcap.mdanderson.org) is 
hosted on a secure server by MD Anderson Cancer Center's Department of Research 
Information Systems & Technology Services. 

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REDCap has undergone a Governance Risk & Compliance Assessment (05/14/14) by 
MD Anderson's Information Security Office and found to be compliant with HIPAA, 
Texas Administrative Codes 202-203, University of Texas Policy 165,  federal 
regulations outlined in 21CFR Part 11, and UTMDACC Institutional Policy #ADM0335. 
Those having access to the data file include the study PI and research team personnel. 
Users are authenticated against MDACC's Active Directory system. All protected health 
information (PHI) will be removed from the data when it is exported from REDCap for 
analysis.  Following publication study data will be archived in REDCap. 
 
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 protected to the best 
of our ability. 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 investigator, collaborators, and research staff will have access to study 
records. 
Data sharing: Study data will not be shared with outside individuals  or entities 
without IRB approval. 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 kept forever in an MD Anderson 
database, combined with other patients’ information in the future, and used for future 
research studies. 
 
 
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