Brief Behavioral Intervention for Dyspnea in Patients With Advanced Lung Cancer
Phase: NA
Conditions: Lung Cancer
Sponsor: Massachusetts General Hospital

Brief Behavioral Intervention for Dyspnea in Patients with Advanced Lung Cancer 
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Brief Behavioral Intervention for Dyspnea in Patients with Advanced Lung Cancer 
DF/HCC SOCIAL-BEHAVIORAL RESEARCH PROTOCOL 
PIs: Joseph Greer & Jennifer Temel 
Massachusetts General Hospital 
ClinicalTrials.Gov: NCT03089125 
Version 1.19 
11/15/2021 
 
Section 1: Protocol Schema 
 
 
 
 

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Section 2: Body of Protocol 
 
Table of Contents 
1.0 INTRODUCTION ................................................................................................................... 3 
1.1 Overview. ........................................................................................................................................................ 3 
1.2 Background and Rationale. .............................................................................................................................. 3 
2.0 OBJECTIVES.......................................................................................................................... 8 
2.1 Primary Aim .................................................................................................................................................... 8 
2.2 Secondary Aim ................................................................................................................................................ 8 
2.3 Exploratory Aim .............................................................................................................................................. 8 
3.0 RESEARCH SUBJECT SELECTION ..................................................................................9 
3.1 Patient Eligibility Criteria................................................................................................................................ 9 
4.0 RESEARCH SUBJECT ENTRY ...........................................................................................9 
4.1 Patient Screening ............................................................................................................................................. 9 
4.2 Patient Recruitment and Enrollment .............................................................................................................. 10 
4.3 Randomization and Registration .................................................................................................................... 12 
5.0 STUDY DESIGN & METHODS ..........................................................................................12 
5.1 Study Design ................................................................................................................................................. 12 
5.2 Selection of Instruments. ............................................................................................................................... 13 
5.3 Description of Intervention ............................................................................................................................ 14 
5.4 Data Collection Procedures ........................................................................................................................... 16 
5.5 Description of Study Processes ..................................................................................................................... 17 
5.6 Adverse Reactions and Their Management ................................................................................................... 21 
6.0 STATISTICAL ANALYSIS ..................................................................................................23 
6.1 Study Endpoints ............................................................................................................................................ 23 
6.2 Sample Size and Power Calculation .............................................................................................................. 23 
6.3 Analysis Plan ................................................................................................................................................. 23 
6.4 Handling of Missing Data.............................................................................................................................. 25 
6.5 Potential Problems, Alternative Strategies and Benchmarks for Success ...................................................... 25 
7.0 REFERENCES .......................................................................................................................27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 INTRODUCTION 
 
1.1 Overview. 
At least 50% of patients with advanced lung cancer experience debilitating dyspnea that is associated 
with worse medical and psychosocial outcomes. The purpose of the present investigation is to test a 
brief behavioral intervention for dyspnea, delivered by oncology nurses within the outpatient cancer 
clinic or virtually via telephone or secure video visit. Through this study, we seek to increase access to 
much needed symptom management for those diagnosed with advanced lung cancers and ideally 
improve patients’ overall quality of life. 
 
The proposed project is being funded by the National Institutes of Health/National Institute of Nursing 
Research. 
 
1.2 Background and Rationale. 
Dyspnea is Debilitating and Highly Prevalent among Patients with Advanced Lung Cancer 
Lung cancer remains the most commonly diagnosed cancer and leading cause of cancer death 
worldwide.24 Dyspnea, a primary symptom of lung cancer, reflects a subjective experience of distress 
or discomfort related to the sensation of breathlessness.25 The presentation of the symptom may vary, 
with patients describing dyspnea as episodic in nature, triggered suddenly upon exertion, or as 
continuous, occurring even at rest.26 Among patients with advanced lung cancer, approximately half 
report experiencing clinically significant dyspnea that interferes with daily life activities.1,2,10 Moreover, 
the symptom tends to worsen in frequency and severity as patients approach the end of life.3-5 Several 
studies have shown a strong association between the severity of dyspnea and worse quality of life, with 
impairments in physical functioning and emotional wellbeing.9-11,27 
 
Dyspnea is Associated with Significant Symptom Burden and Psychological Distress 
In addition to poor quality of life, dyspnea is linked to increased pain, anxiety, and mood disturbance 
among patients with cancer. In a cohort of 120 patients with early and late-stage lung cancers, 
approximately 87% reported experiencing dyspnea, and those with more severe symptoms also had 
worse pain and anxiety.27 For some individuals, dyspnea is associated with feelings of panic and 
impending death.8 We found in our own investigation of patients with lung cancer that those with 
dyspnea were twice as likely to have panic attacks compared to those without respiratory symptoms.28 
Furthermore, investigators have observed that dyspnea is related to depression, anxiety, fatigue, cough, 
and decreased coping capacity in patients with cancer receiving palliative care services.29 These studies 
underscore that the experience of dyspnea is multifaceted, involving physical and psychological factors, 
and requires comprehensive symptom assessment and management. 
 
Dyspnea is Associated with Increased Service Utilization 
Compounding the suffering experienced by patients and families, dyspnea is a major cause of 
healthcare utilization among individuals with cancer. Specifically, respiratory distress accounted for 
the greatest number of emergency department (ED) visits in patients with lung cancer (32% of visits) 
in one study of cancer-related ED utilization. Many of these patients were subsequently admitted to the 
hospital after ED evaluation.13 This trend persists throughout the course of disease, as dyspnea is the 
second most common reason for visits to the ED in the final two weeks of life for patients with cancer.12 
Data suggest that the median survival for patients with lung cancer who present to the ED with dyspnea 
is only four weeks.30 In the ambulatory care setting, one study showed that over half of patients with 
lung cancer (57%) utilized many services across disciplines, such as pulmonary rehabilitation and 
physical therapy, given their high symptom burden.31 Thus, the Quality Oncology Practice Initiative of 

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the American Society of Clinical Oncology has identified the assessment and management of dyspnea 
as a key measure of quality cancer care.14 
 
Novel Treatment Approaches for Dyspnea Are Greatly Needed 
Despite the significant burden dyspnea represents, data are lacking to support effective treatments in 
patients with cancer.16,17 Opioids have the strongest evidence base, though the medications tend to have 
modest benefit and carry serious risks and side effects.32 Systematic reviews show no improvement in 
cancer-related dyspnea from either supplemental oxygen or benzodiazepines.18,33,34 Although our 
research team found improvements in quality of life and mood among patients with metastatic lung 
cancer by the early integration of palliative care services, this model of care did not affect anxiety 
symptoms or dyspnea.19 Non-pharmacological approaches for dyspnea have included supportive 
counseling, breathing control, muscle relaxation, coping strategies, energy conservation, and 
acupuncture.17 Few clinical trials of these methods exist, and the resulting data appear to be mixed 
across techniques. Yet, interventions that include behavioral elements, such as breathing retraining 
combined with psychoeducation, have shown some promise and warrant further study.20-22 
 
The management of dyspnea due to advanced lung cancer may be ideally accomplished by a 
multidisciplinary team, given the complex interplay of biomedical and psychosocial factors.35 In fact, 
the National Health Service in the United Kingdom has recently developed an approach for managing 
dyspnea across multiple disease states that includes diverse caregivers: physicians, clinical nurse 
specialists, physical therapists, respiratory therapists, occupational therapists and social workers.36 
Although a well-designed randomized controlled trial of the comprehensive program yielded 
significant improvements in breathlessness mastery and survival, the approach involved numerous 
clinic visits with multiple specialists.37 In the U.S., the lack of professionals trained in behavioral and 
palliative medicine severely limits the dissemination of such complex, comprehensive services.38,39 
Novel models of care that address the medical and psychosocial aspects of dyspnea in a feasible, 
acceptable, and seamless manner within outpatient settings may prove more beneficial and scalable. 
 
MGH Cancer Center Sites/DFCI Are Ideal Clinical Settings for Collaborative and Cross- 
Disciplinary Research 
At the Massachusetts General Hospital (MGH) Cancer Center, we have gained considerable experience 
in multidisciplinary research in the oncology setting. Our Cancer Outcomes Research Program consists 
of oncologists, nurses, palliative care physicians, psychiatrists, and psychologists who share their 
respective expertise to inform the development of state-of-the-art clinical interventions to improve 
comprehensive cancer care, symptom management, and quality of life for patients with cancer. In 
addition to establishing highly successful methods for recruiting and retaining patient participants, we 
have capitalized on our cross-disciplinary collaborations to overcome barriers in communication, 
coordination, and integration of supportive care services into the outpatient oncology setting. With 
external funding from federal and nonprofit organizations, we have conducted numerous studies 
demonstrating improved patient and provider outcomes with interventions such as: early palliative care 
services;19 clinician-directed prompts for discussing end-of-life care preferences;40 the adaptation of 
cognitive-behavioral therapy to treat anxiety related to advanced cancer;41 and training of oncology 
nurses in psychological skills to manage stressful patient and family encounters,42 among others. 
 
Recognizing the limited availability of such unique collaborative teams across cancer centers, we seek 
to test novel models of care that can be widely accessible and feasible to implement. We therefore have 
partnered with the Dana-Farber Cancer Institute (DFCI) and their leading nurse researcher in symptom 
management (Dr. Cooley) to test our proposed dyspnea intervention. We will train oncology nurses at 
both sites to deliver behavioral techniques shown to be effective for breathing retraining and reducing 
distress. Nurses are well-qualified for administering this type of intervention as they are integrated in 

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the oncology care setting, can assess both the medical and psychosocial factors associated with dyspnea, 
and provide expert symptom management. 
 
Theoretical Basis of Proposed Brief Behavioral Intervention for Dyspnea 
The experience of dyspnea involves interactions among physical, psychological, and social factors.43 
We therefore propose to test the efficacy of a brief behavioral intervention to reinforce adaptive coping 
responses to dyspnea. Leading investigators of cognitive-behavioral therapy (CBT) have posited that a 
combination of biological factors and stressful 
life events can result in maladaptive distress 
through an interactive cycle of physiological, 
cognitive, and behavioral symptoms. The 
primary features of this cycle include increased 
autonomic 
arousal, 
negative 
biases 
in 
perception, and avoidance of threatening 
stimuli.44 Moorey et al.45 further elaborated the 
CBT model to understand the ways in which 
individuals adjust to having cancer. They argue 
that cancer and its symptoms (e.g., dyspnea) 
represent a legitimate sense of danger to one’s 
physical and social well-being, triggering 
vulnerability in one’s beliefs about being able 
to  cope  with  this  threat.  Noting  the  bi- 
directional relationships among physiology, cognition and behavior, the theorists suggest in their 
Cognitive Model of Adjustment to Cancer that schemas related to the self (i.e., view of the self) and to 
survival (i.e., view of the disease, degree of control over cancer and its symptoms) play central roles in 
the maintenance of distress. Given the legitimate threat to survival and changes in self-schema due to 
the symptoms of advanced lung cancer, the dyspnea intervention has been tailored to incorporate 
strategies for managing the complex interplay between the medical and psychological concerns. 
Targeting each domain, the intervention includes 1) psychoeducation to enhance cognitive 
understanding of dyspnea, 2) relaxation practice to reduce physiological stress, and 3) behavioral 
coping skills for managing acute dyspnea. 
 
Summary of Significance 
The proposed study is significant in that it targets the markedly prevalent and burdensome symptom of 
dyspnea with a brief nurse-administered behavioral intervention that has potential for cost-effective 
scalability and broad dissemination across cancer care settings. Furthermore, the intervention 
techniques are evidence-based and derived from sound theory, providing significant clinical benefit 
with minimal burden of care to patients. 
 
Preliminary Studies 
Rate of Dyspnea is High in Patients with Non-Small Cell Lung Cancer and Associated with 
Distress.28 
Our team explored the frequency of dyspnea and the risk of panic disorder and depression symptoms 
among patients with newly diagnosed non-small cell lung cancer (NSCLC). Consecutive patients 
presenting for initial consultation at the Massachusetts General Hospital Thoracic Oncology Clinic 
completed a survey of current symptoms, including dyspnea, panic disorder, and depression symptoms. 
Among 624 patients (mean age=63.7; SD=12.1; 52.6% female), 48.1% reported at least moderate 
dyspnea. Dyspnea was independently associated with higher risk of panic disorder symptoms (odds 
ratio=2.19, 95% CI=1.11-4.31, P=0.02). Younger age and major depression symptoms were also 
associated with higher risk (P<0.01). In conclusion, almost half of the patients with newly diagnosed 

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non-small cell lung cancer reported dyspnea, and patients with dyspnea were more than twice as likely 
to endorse panic disorder symptoms relative to patients without dyspnea. 
 
A Tailored Cognitive-Behavioral Intervention Alleviates Anxiety in Patients with Terminal 
Cancer.48 
For this NCI-funded randomized trial (R03CA128478, PI: Greer), we used mixed methods to examine 
the feasibility and preliminary efficacy of cognitive-behavioral therapy (CBT) to reduce anxiety in 
patients with terminal cancers. Based on qualitative feedback from patients, we adapted the CBT 
intervention by developing treatment modules for relaxation, coping with cancer worries, and activity- 
pacing. Adults with incurable malignancies and elevated anxiety (Hamilton Anxiety Rating Scale; 
HAM-A>14) were then randomized to individual CBT or a wait-list control group. Primary outcomes 
included: 1) the number of completed CBT visits, and 2) change in HAM-A scores from baseline to 8- 
week follow up per a treatment-blind evaluator. Forty patients with terminal cancers were randomized 
(CBT n=20, Wait-list Control n=20), and 80% of CBT patients completed at least 5 of the 6 sessions. 
Of the total 109 completed CBT sessions, 45 (41.3%) occurred either on the same day as other hospital 
appointments (n=25, 22.9%) or during chemotherapy infusions (n=20, 18.3%). Linear regression 
analyses, adjusted for baseline scores, showed that those assigned to CBT had greater improvements in 
HAM-A scores compared to the control group (Adjusted Mean Difference=-5.42; 95% CI=-10.84, - 
.001; p=.05), with a large effect size for the intervention (Cohen’s d=.80). Providing CBT tailored to 
the concerns of patients with terminal cancer was not only feasible but also led to significant 
improvements in anxiety. 
 
Nursing Interventions Are Feasible for Symptom Management in Patients Receiving 
Chemotherapy.49 
Drs. Temel and Greer recently completed a RCT of a proactive nursing intervention to improve 
symptom management after chemotherapy administration in patients with early stage lung, breast and 
colon cancer. We enrolled and randomized 120 of 137 eligible patients (88%). Those in the intervention 
group (n=60) received twice weekly phone calls from an oncology nurse after the patients’ first two 
chemotherapy infusions. Only two patients withdrew from the study and did not complete post-study 
assessments. Although the study showed no differences between groups in the primary outcomes, it 
nonetheless demonstrates the feasibility of enrollment, retention, and collection of patient-reported 
measures within the context of nursing intervention trials. 
 
A Brief Nurse-Administered Intervention Reduces Dyspnea in Patients with Advanced Lung 
Cancer.23 
We examined the feasibility, acceptability, and utility 
of delivering a brief behavioral intervention for 
dyspnea in patients with lung cancer at the point of 
care. For this single-group pilot trial, eligible patients 
included those with advanced lung cancer (stage III 
or IV non-small cell [NSCLC] or extensive stage 
small cell [SCLC]) from the ambulatory care clinic 
who reported at least moderate breathlessness. The 
manualized intervention consisted of two sessions in 
which 
nurse 
practitioners 
taught 
participants 
breathing and relaxation techniques within the 
infusion clinic and encouraged home practice. 
Participants 
completed 
measures 
of 
dyspnea 
(Modified Medical Research Council Dyspnea Scale 
[MMRCDS]), QOL (Functional Assessment of  
Illustrative Patient Quotations 
• “It was convenient because it was during 
the appointments, and it wasn’t too long. I 
thought it was an excellent use of time, and 
it was integrated very nicely with what was 
going on.” 
• “The [breathing exercises] helped me when 
if I started to lose my breath, to really slow 
myself down, instead of taking shallow 
breath to my lungs, I learned to hold all the 
air in and then let it back out and fill my 
lungs faster than taking short little breaths, 
and I found that was the most helpful part 
of the program.” 
• “The nurse was engaging and very good at 
responding to and expanding on any kind of 
question I had.” 

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Cancer Therapy-Lung Trial Outcome Index [FACT-L TOI]), and anxiety and depression symptoms 
(Hospital Anxiety and Depression Scale [HADS]) at baseline and six weeks post enrollment. Of the 
32 patients enrolled in the study (56.3% Female; Mean Age=63.34, SD=7.96 years), 84.4% (N=27) 
completed all study procedures. Comparing the baseline to post-assessments, we found significant 
improvements in MMRCDS (p<.001), FACT-L TOI (p=.01), and HADS-Depression Subscale 
(p<.001) scores, with corresponding moderate to large effect sizes. In this sample of patients with 
advanced lung cancer, we observed a high completion rate for the two- session intervention. Patients 
also reported improvements in dyspnea, QOL, and distress. Based on participant exit interviews (see 
illustrative quotes), 95.5% of patients rated the intervention favorably for its convenient location of 
delivery, low burden, effective coping skills, and positive social support. 
 
Measuring Performance Status with Actigraphs Correlates with Dyspnea in Patients with 
NSCLC.47 
Dr. William Pirl recently completed a pilot study to evaluate the feasibility of using actigraphy to 
measure performance status in 42 patients with metastatic NSCLC. Participants wore wrist actigraphs 
for three days prior to completing questionnaires assessing symptoms, including dyspnea, and their 
activity level. Eastern Cooperative Oncology Group performance status (ECOG PS) has a clinically 
meaningful difference in scores based on whether a patient is inactive for at least half the time they are 
awake. Actigraphy objectively captures the percentage of time a person is immobile but awake. 
Actigraph reports of participants’ percent time spent immobile but awake ranged from 4-50% 
(Mean=18%, SD=11%). Percent of time awake and spent immobile was correlated with physician 
report of ECOG PS (r=0.44, p=.004). Patient-reported dyspnea on the FACT-L was associated with 
three assessments of physical functioning: physician report of ECOG PS (r=-0.52, p<.001); patient- 
reported walking speed (r=-0.51, p=.001); and percent of time awake and spent immobile (r=-0.36, 
p=.02). Based on our findings, we will use actigraphy as an objective measure of physical activity in 
the current study. 
 
Summary of Preliminary Studies: For the past decade, our team has successfully collaborated on 
numerous supportive care studies for patients with lung and other cancers. The above studies highlight 
our accomplishments in demonstrating the need to treat dyspnea; developing and testing behavioral 
interventions in cancer; implementing nurse-administered symptom management trials; and using 
novel technologies for assessment. 
 
Innovation of Proposed Study 
The proposed study is innovative with respect to the 1) novel model of delivering the intervention 
at the point of care within outpatient oncology setting, and 2) multimethod assessment of patient 
outcomes. Given that patients with advanced lung cancers can be quite ill, the burden of additional 
appointments for behavioral treatment of symptoms represents a significant barrier to accessing 
services. Thus, we propose to address this concern by administering a point-of-care intervention that 
involves cross-disciplinary training and delivery within the flow of oncology care. The PI team is 
uniquely qualified to oversee such a program. Drs. Greer, Temel, and Cooley possess expertise in 
behavioral medicine/cognitive-behavioral therapy, thoracic oncology/palliative care, and nursing 
practice/cancer symptom management, respectively. This team will train and supervise the oncology 
nurses in delivering the evidence-based dyspnea management intervention. We elected to develop a 
minimally intensive behavioral intervention that can be easily implemented, involves home-based 
practice, and avoids barriers to scheduling multiple outpatient visits, especially for those suffering from 
considerable symptom burden. Specifically, we are proposing a streamlined dyspnea management 
intervention, to be completed over two 30-45minute sessions in tandem with outpatient clinic 
appointments or virtually via telephone or secure video visit. Although recent studies have shown 

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benefit from more complex, multi-component, intensive interventions for dyspnea,37,46 such approaches 
require considerable clinician resources and time, which are neither scalable nor feasible for patients 
with advanced cancer undergoing burdensome treatments. Moreover, we observed in our prior study 
that patients greatly appreciated being able to meet with the nurse interventionists and learn the 
behavioral skills in the infusion clinic rather than having to make extra visits to the hospital.23 Thus, 
providing the brief intervention at the point of care in the outpatient oncology setting or virtually 
represents a new model of cancer care that is feasible for implementation outside a grant-funded 
environment. Such an approach could be easily deployed to larger populations. 
 
Finally, in addition to measuring self-report outcomes of dyspnea, quality of life, anxiety and 
depression, we will assess the effect of the brief intervention on functional status using actigraphy. We 
have piloted the use of actigraphy in the study population (see Preliminary Studies), observing strong 
correlations between self-reported dyspnea and objective activity levels in patients with metastatic lung 
cancer. To our knowledge, no prior studies have incorporated this multimethod approach to evaluating 
dyspnea intervention outcomes, which could serve as a new, state-of-the-art methodology for 
measuring performance status in patients with cancer. 
 
 
2.0 OBJECTIVES 
 
2.1 Primary Aim 
To demonstrate the efficacy of the brief behavioral intervention for improving self-reported dyspnea 
(primary outcome) in patients with advanced lung cancer 
Hypothesis: Participants with advanced lung cancer who are randomly assigned to receive the brief 
behavioral intervention will report statistically and clinically significant improvements in dyspnea 
compared to those assigned to usual care. 
 
2.2 Secondary Aim 
To demonstrate the efficacy of the brief behavioral intervention for improving patient quality of life, 
mood symptoms, and activity level (secondary outcomes) in patients with advanced lung cancer 
Hypothesis: Participants with advanced lung cancer who are randomly assigned to receive the brief 
behavioral intervention will experience statistically and clinically significant improvements in quality 
of life, mood symptoms, and activity level compared to those assigned to usual care. 
 
2.3 Exploratory Aim 
To explore mediators and moderators of the effect of the brief behavioral intervention on patient- 
reported outcomes 
Hypothesis: Intervention effects on patient-reported dyspnea will be mediated by improved mastery in 
managing breathlessness and potentially moderated by patient demographic and clinical factors (e.g., 
gender, age, performance status, and disease comorbidity). 
 
 
3.0 RESEARCH SUBJECT SELECTION 
 
3.1 Patient Eligibility Criteria 
 
3.1.1 Inclusion Criteria 
The patient eligibility criteria will mirror those in our successful pilot study.23 To be eligible for 
the RCT, patients must have: 
1) A diagnosis of either NSCLC, SCLC, or mesothelioma, not being treated with curative intent 

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2) Self-reported shortness of breath (a score of 2 or greater on the Modified Medical Research 
Council Dyspnea Scale) 
3) Eastern Cooperative Oncology Group (ECOG) Performance Status from 0 (asymptomatic) to 2 
(symptomatic and in bed <50% of day) 
4) The ability to respond to questions in English 
5) Primary cancer care at the Massachusetts General Hospital (MGH) Cancer Center, Dana- 
Farber Cancer Institute (DFCI), Mass General Cancer Center at Newton-Wellesley Hospital, and 
Mass General/North Shore Cancer Center-Danvers 
6) Age >18 years 
 
3.1.2 Exclusion Criteria 
Patients will be excluded if they have: 
1) Cognitive or psychiatric conditions prohibiting study consent or participation. 
2) A treating clinician who reports that the patient is inappropriate for the study 
 
 
4.0 RESEARCH SUBJECT ENTRY 
 
4.1 Patient Screening 
In our pilot study, we asked clinicians to identify patients with dyspnea by reviewing their clinic 
schedules at the weekly thoracic oncology staff meeting. While we enrolled study participants 
rapidly in the pilot study, this recruitment method required the clinician to have knowledge of 
patients’ dyspnea. However, oncology clinicians often fail to recognize or underestimate dyspnea.50 
Thus, relying on clinician awareness of patients’ symptoms is unlikely to identify all eligible 
patients for study participation. Therefore, in the current proposal, we will identify patients for 
study participation based upon their self-report of dyspnea using a validated standard screening 
measure (i.e., MMRCDS). We will institute the same patient screening procedures in the 
participating thoracic oncology clinics at Massachusetts General Hospital, Dana-Farber Cancer 
Institute, Mass General Cancer Center at Newton-Wellesley Hospital, and Mass General/North 
Shore Cancer Center-Danvers as we share the same scheduling and health record systems. As a 
point-of-care intervention, we will screen all patients with lung cancer receiving care in the 
outpatient clinics and approach them in person or via telephone. By reviewing the electronic 
scheduling system and health record module documenting cancer stage, we will identify all patients 
with advanced lung cancer who are scheduled for visits in the subsequent week. 
 
A partial HIPAA Authorization will be obtained for the collection of protected health information 
(PHI) prior to consent. The waiver will allow the study staff to identify potential eligible patients 
to recruit and contact. It will also prevent ineligible patients from being contacted and burdened 
with an in-person or telephone screen for a study for which he or she would be ineligible. 
Additionally, the waiver would allow patients to be screened with the MMRCDS prior to consent, 
reducing any emotional distress associated with consenting to a study for which they are potentially 
ineligible. Having access to PHI will both optimize patient recruitment opportunities, while 
decreasing burden on ineligible patients. The use and disclosure of this information does not 
involve more than a minimal risk to privacy. 
 
The study staff will review and collect information on the cancer diagnosis, stage, date of outpatient 
oncology clinic appointments, Eastern Cooperative Oncology Group (ECOG) Performance Status, 
age, language, phone number and patients’ self-reported MMRCDS score before administering 
consent. Information collected from screened patients will be stored in a password-protected 
computer file that is stored on a secure, HIPAA-compliant Partners network drive. Only 

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information relevant for contacting and screening the participants will be stored on this database. 
This secure procedure will prevent any improper use and disclosure of PHI. 
 
For patients who screen eligible on the MMRCDS (shortness of breath ≥ 2 on MMRCDS), their 
data will be scanned and securely stored in a secure, HIPAA-compliant Partners network drive. For 
patients who do not screen eligible on the MMRCDS, their data on this measure will be destroyed 
immediately. For more information on the protection of patient data, see section 5.5.3. 
 
Before approaching the patients meeting the above criteria, the study staff will inform the oncology 
health care team (i.e., oncologist, advanced practice nurse, palliative care specialist as appropriate) 
of their patient’s potential eligibility for study participation via email or in person. The study staff 
will also notify the cancer care team of their plan to approach the patient regarding study 
participation at the next scheduled visit or via telephone should the team not respond with any 
reservations. Clinicians who express that they do not wish to receive these emails will be 
approached in clinic for permission to discuss study participation with patients. All other clinicians 
will be sent an email containing the patient’s name and medical record number and the request for 
study staff to approach the patient. A member of the cancer care team will be informed at least two 
business days prior to approaching the patient for the first time. If a clinician prefers that we do not 
approach her or his patient for study participation, we will collect the reason for this request. 
Finally, we will state in the email or in person that study participation does not preclude the 
clinicians from medically treating the dyspnea per their clinical judgment. 
 
Once the oncology health care team has been informed and has not refused study staff to approach 
their patient, a study staff member will approach the patient in the infusion unit outpatient clinic, 
or via telephone to inquire about their experience with dyspnea. If the patient reports having 
dyspnea, the trained study staff member will explain the study. If the patient indicates interest in 
the study, they will be asked to complete a brief single-item screen to determine if they meet 
eligibility criteria (i.e., shortness of breath ≥ 2 on MMRCDS) for participation. To decrease 
participant burden, this brief screening measure will be given prior to consent. For patients who are 
approached via telephone, the MMRCDS will be administered verbally, via mail, or electronically. 
If the patient screens ineligible, the patient will not be consented and their MMRCDS will be 
appropriately discarded by the study staff using HIPAA-compliant procedures immediately. 
Patients who report shortness of breath score of ≥2 on the MMRCDS breathlessness measure will 
be eligible to continue to the next stage of the study. 
 
For patients who screen eligible on the MMRCDS, the trained study staff member will perform 
consent procedures and administer the baseline assessments. Following the completion of the 
baseline assessments, the patient will be randomized to receive the intervention or standard care. 
 
Otherwise, given that patients with advanced lung cancer develop new symptoms over time, 
patients with a score of <2 on the MMRCDS who agree to be approached again will continue to be 
screened with the brief measure every three months. 
 
4.2 Patient Recruitment and Enrollment 
After the oncology care team has been informed and has not refused study staff to approach their 
patients, a trained study staff member will contact potential participants in-person or via telephone 
to explain the study and offer a brief screen to confirm whether the patient is eligible to participate. 
If an oncology clinician reports that the patient is being treated with curative intent or otherwise 
does not meet eligibility criteria, study staff will document the reason. If eligible, the informed 
consent process may be completed through either modality as detailed in this section. Both the 

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written and the verbal consent forms describe all study procedures, information about potential 
risks and benefits of participation, and information regarding who they can contact for further 
questions. The forms also state that participation is voluntary, that participants can refuse to answer 
any questions, that they can withdraw from the study at any time, and that study participation is in 
no way related to their medical care. Study participants who do not provide consent will be asked 
the reason why they prefer to not participate in the study. All willing participants that provide 
consent will then be registered by study staff (see below). 
 
4.2.1 In-Person Informed Consent Process 
Participants will be asked to complete the MMRCDS scale evaluating shortness of breath 
to confirm that their breathlessness is sufficient to participate (as discussed in section 4.1). 
All patients who screen positive on the MMRCDS shortness of breath measure (i.e., a score 
of ≥ 2 on the MMRCDS) will be considered eligible for the study. 
 
After confirming eligibility based on the MMRCDS, the study staff will then perform 
consent procedures by presenting the patient with a detailed, HIPAA-compliant consent 
form to be signed by each participant following the explanations by the study staff. 
 
4.2.2 Verbal Informed Consent Process 
We are requesting an alteration of HIPAA to allow for a waiver of Written 
Documentation of Consent. This study meets the requirements for a waiver as it is a 
Minimal Risk study and all study procedures can be communicated verbally. The verbal 
consent procedures can accommodate external factors such as safety concerns for patients 
or study staff, hospital guidelines, a lack of clinic space or patient time constraints. 
Patients are coming into the hospital less regularly to receive in-person care, which limits 
our ability to approach them onsite for consent procedures. Remote electronic consenting 
is not feasible for many patients in our population as it requires technology and technical 
skill that some patients lack, potentially leading to a selection bias among enrolled 
participants. Consenting by mail is also not feasible given the patient population has 
advanced lung cancer with a poor prognosis and mailing the consent form to and from the 
participant would likely create delays in enrollment of several weeks negatively 
impacting enrollment, retention and completion of study procedures. Verbal consent 
reduces patient burden and attrition and allows for greater flexibility while assuring 
patient safety in response to changing healthcare practices due to the COVID-19 
pandemic. 
 
A study staff member will contact the patient via telephone to offer study participation 
and determine eligibility using the recruitment and screening script. Patients who screen 
positive on the MMRCDS shortness of breath measure (i.e., a score of ≥2 on the 
MMRCDS) will undergo verbal consent procedures using the suggested verbal phone 
script provided within the HIPAA-compliant verbal consent form. All patients who 
provide verbal consent will receive an unsigned copy of the written informed consent. If 
the patient does not answer the phone, the clinician or study staff member may leave a 
voicemail (see appendix 8.11 for suggested language for the voicemail). 
 
 
4.2.3 Baseline Completion 
Patients will be asked to complete the baseline questionnaires in person, via mail, 
telephone, or electronically. Once patients complete baseline questionnaires, the study staff 
will provide them with a wrist actigraph and activity log. Patients will be instructed on the 

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proper use of the actigraph and told to wear it and complete the activity log for the 
following 3 days. When this 3-day period ends, a study staff member will call the 
participant and notify them of their study group assignment. Patients will either return the 
actigraph at their next clinic visit or will mail it back to study staff via FedEx paid for by 
the study. 
 
Using data from our electronic billing systems, we estimate that approximately 480 patients 
with advanced lung cancer receive treatment at the MGH Cancer Center and DFCI per 
year. Although studies show that approximately 50% of patients with metastatic cancer 
endorse some degree of shortness of breath, we conservatively anticipate 30%-40% of 
patients will report shortness of breath ≥2 using the MMRCDS (resulting in approximately 
140-190 eligible patients per year). Based on the high accrual rates observed in our 
previous supportive care studies, and low patient burden for the proposed trial, we estimate 
60% accrual to this study. Thus, we will be able to achieve successfully our recruitment 
goal of 220 patients during the 4-year enrollment period. 
 
4.3 Randomization and Registration 
MGH Biostatistical Core will be responsible for generating one randomization scheme. 
Randomization will be stratified by cancer type (NSCLC versus SCLC versus mesothelioma) and 
study site (Massachusetts General Hospital Cancer Centers versus Dana-Farber Cancer Institute). 
 
The registration and randomization procedures are as follows: 
• 
Obtain written informed consent or verbal consent from the participant prior to the performance 
of any protocol specific procedures or assessments. 
• 
Complete the protocol-specific eligibility checklist using the eligibility assessment documented 
in the participant’s medical record and/or research chart. To be eligible for registration to the 
protocol, the participant must meet all inclusion and exclusion criteria as described in the 
protocol and reflected on the eligibility checklist. 
• 
The DFCI study staff will confirm eligibility criteria and fax or email the following documents 
to the study staff at MGH: deidentified signed consent form/s and a completed eligibility 
checklist. 
• 
A member of the MGH study staff (independent from study staff who recruit, enroll and 
administer assessments to participants) will perform randomization procedures using a 
randomization schema stratified by cancer type and study site. 
• 
The MGH study staff will fax or email the information about randomization to the study staff 
at DFCI. The MGH study staff may also call the study staff at DFCI to verbally confirm 
registration and randomization. 
• 
Both MGH and DFCI will register eligible participants from all sites in the Clinical Trials 
Management System (CTMS) Oncore, as required by DF/HCC Standard Operating Procedure 
for Human Subject Research Titled Subject Protocol Registration (SOP #: REGIST-101). This 
must occur prior to the initiation of protocol-specific procedures or assessments. 
 
 
5.0 STUDY DESIGN & METHODS 
 
5.1 Study Design. 
We will conduct a randomized controlled trial (RCT) of a brief two-session behavioral intervention 
for dyspnea management in patients with advanced lung cancer. 
 
5.2 Selection of Instruments. 

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We selected instruments based on our theoretical framework of the intervention, which seeks to 
reduce dyspnea sensations (physiological), improve understanding and perceptions of mastery in 
coping with the symptom (cognitive), as well as enhance activity/performance status (behavioral). 
 
Outcome Measures: 
Modified Medical Research Council Dyspnea Scale (MMRCDS): The MMRCDS is a one-item 
scale with a 5-point grading system to evaluate patients’ degree of dyspnea.59,60 
 
Cancer Dyspnea Scale (CDS): The CDS is a twelve-item scale that assesses the multidimensional 
nature of dyspnea in cancer patients. 72 
 
Functional Assessment of Cancer Therapy-Lung (FACT-L): The FACT-L quality of life tools 
assess physical, social/family, emotional, and functional well-being (27 items) and lung cancer 
specific symptoms (8 items) over the past 7 days.61 
 
Hospital Anxiety and Depression Scale (HADS): The HADS assesses symptoms of anxiety (7 
items) and depression (7 items) over the previous week.62 
 
Godin-Shephard Leisure Time Physical Activity Questionnaire (GSLTPAQ): The GSLTPAQ is a 
brief assessment of the frequency and the extent of typical exercise during free time over the course 
of one week (4 items).63 
 
Potential Mediator and Moderators of Intervention Effect 
Chronic Respiratory Disease Questionnaire (CRQ): The CRQ is a validated 20-item measure that 
assesses physical and psychological aspects of chronic respiratory disease including “mastery,” or 
perceptions of control over the disease, and its effects on quality of life and functioning.64,65 
 
Eastern Cooperative Oncology Group Performance Status (ECOG PS): Study participants will be 
asked to choose the functional rating which best describes their performance status in the past 
week.66 
 
Demographic Questionnaire: Participants will self-report their age, sex, race/ethnicity, marital 
status, religion, education level, and tobacco use (both prior and current use) at baseline.  On 
8/20/2017, we amended this questionnaire to include two questions about tobacco use. For all 
patients who completed baseline prior to this date, we will administer the two tobacco use questions 
at the next assessment point (week 8, week 16, or week 24). 
 
Objective Performance Status Measure 
Wrist Actigraphs: An actigraph is a portable, wristwatch-sized accelerometer device that detects 
and logs wrist movement over time in the form of activity counts. We will use Spectrum Plus 
(Philips Respironics USA), which is a watch-sized device that can be worn 
comfortably during activities of daily living, including sleeping, bathing, and 
exercise. Spectrum Plus detects and logs wrist movement to measure physical 
activity and has a light sensor to determine day and night time hours. Spectrum 
Plus has a rechargeable battery and is fully waterproof. Data from Spectrum 
Plus are retrieved using specialized software. Study participants will also 
receive a 3-day activity log to complete while wearing the actigraph to 
supplement the recording of their activity level and confirm their sleep/wake 
schedule. Patients will record the times they woke up, got out of bed, napped, 
went to bed, and turned out the lights each day while wearing the actigraph. All study participants 

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will be given an Spectrum Plus and activity log at the time of completing the baseline assessment. 
Participants will be asked to wear the actigraph and complete the activity log for two 3-day periods 
during the study, at baseline and week 8. The study staff will explain that the actigraph should be 
worn on their non-dominant wrist continuously for each 3-day period, including while bathing and 
exercising. The study staff will contact participants via telephone to remind them when to begin 
using the actigraph and activity log. In our previous study assessing the feasibility of using the 
actigraph in patients with metastatic lung cancer, all study participants wore the actigraph for the 
full 3-day period and completed the activity log.47 
 
5.3 Description of Intervention 
 
5.3.1 Clinician Training and Supervision 
In our prior pilot study, we created a clinician manual that includes step-by-step 
instructions for teaching the behavioral strategies for managing dyspnea. This manual was 
developed and partially adapted from an evidence-based cognitive-behavioral treatment 
for anxiety in patients with advanced cancer.48,51 Given that a primary aim of the proposed 
study is to improve access to care for patients, we will train oncology nurses (at each study 
site) in the administration of the brief intervention for delivery in the outpatient and 
infusion clinics or virtually via telephone or secure video visit. We will use HIPAA- 
compliant, hospital-approved Zoom videoconferencing. The study nurses will first review 
the manual and then participate in a comprehensive didactic training session with the PI 
team (i.e., Drs. Greer, Temel, and Cooley) to reinforce learning of the intervention 
components as well as to clarify the process for administering the intervention within the 
outpatient setting or virtually via telephone or secure video visit. The training sessions will 
include practicing and role playing the delivery of the intervention with Dr. Greer, who is 
a licensed clinical health psychologist with expertise in developing and testing cognitive- 
behavioral interventions for patients with cancer. Once the randomized trial begins, the 
study nurses will be asked to complete an intervention guide/checklist detailing the 
exercises for use in session and to document administration of the intervention components 
with each participant. Drs. Greer, Temel, and Cooley will also hold regular, ongoing 
teleconference calls with the nurse interventionists to provide supervision, address any 
participant concerns that arise, and reinforce protocol adherence. At least 80% of the 
intervention sessions will be audio-recorded to allow for circumstances with unexpected 
technological difficulties. We will randomly select 10% for Dr. Greer (or trained study 
staff member) to review to ensure fidelity 
 
5.3.2 Delivering the Dyspnea Management Intervention 
Patients assigned to the brief behavioral intervention for dyspnea will participate in two 
sessions. Sessions one and two will be administered in-person, via telephone, or via 
institution approved secure videoconferencing technology. 
 
Session One: The first session of the brief behavioral intervention consists of having the 
patients learn evidence-based approaches for dyspnea management including: 1) 
psychoeducation, 2) relaxation training for reducing physiological stress, and 3) behavioral 
techniques for managing acute breathlessness.20 For the psychoeducation component, the 
study nurses will provide participants with a brief overview of the cognitive-behavioral 
model and describe how breathlessness activates the physiologic stress response. 
Specifically, the nurse will explore with the patient the types of thoughts that breathlessness 
triggers (e.g., “I can’t get enough air; my cancer must be getting worse”) and associated 
physiologic (e.g., chest tightness, heart racing) and behavioral responses (e.g., avoiding 

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strenuous activity or physically demanding tasks) that perpetuate stress, deconditioning 
and worsening dyspnea. The nurses will discuss in detail the nature of the stress response 
to help the patients understand the physiologic changes in their body as a result of 
breathlessness and to empower them to use coping strategies to calm the body. Next, 
patients will learn to manage acute breathlessness with several evidence-based techniques 
including pursed-lips breathing,52 use of a battery-operated handheld fan (blowing air 
toward the face),53 and postural techniques to minimize work of breathing.54,55 Commonly 
used for chronic obstructive lung disease,56 pursed-lips breathing provides natural 
resistance to lengthen the exhalation phase, strengthen respiratory muscles, and release 
“trapped” air from the lungs. Finally, as a daily practice to reduce overall physiological 
stress, participants will receive training in relaxation exercises, including diaphragmatic 
breathing and guided breathing meditation.57,58 Individuals who are unable to take full, 
deep breaths due to severe lung disease may modify diaphragmatic breathing by focusing 
on slowing the breath and extending the expiratory phase rather than taking deep 
inhalations. The study nurses will instruct patients to practice these relaxation exercises 
every day at times when not experiencing acute dyspnea. Participants will receive 
instructional pamphlets, handheld fans, and audio-recordings of the guided breathing 
exercise for daily practice. Participants will receive study intervention materials in-person, 
via mail or email. Participants with smart phones will be able to download the recorded 
exercises to their phones, while those without this technology will receive MP3 players 
with recordings of the exercises. 
 
Session Two: The second session of the dyspnea intervention will focus on patients’ 
adherence to the study protocol, review of home-based practice of techniques for acute 
dyspnea and breathing exercises, identification and problem-solving of any obstacles to 
practicing the intervention techniques, and reinforcement of information and behavioral 
skills covered in session one. Sessions one and two will take place approximately 2-3 
weeks apart and will last no more than 30-45 minutes, as we observed in our prior trial. 
Participants may complete this session in person or virtually via telephone or secure video 
visit. 
 
5.3.3 Usual Care 
Patients in both study groups may receive any usual care for their dyspnea as deemed 
appropriate by their clinicians. Cancer care clinicians commonly prescribe opioids, 
benzodiazepines and nasal canola oxygen for patients with dyspnea, though these 
interventions tend to have minimal benefit. In addition, some patients may undergo 
procedures for pulmonary complications that can impact their respiratory status, including 
draining pleural effusions and stent placement or radiation therapy for bronchial 
obstructions. MGH and DFCI Pulmonology clinicians will provide consultative guidance 
for the investigative team on such cases in the study, regardless of group assignment. While 
the study staff will track medical therapies and procedures through the electronic health 
record for patients in both study groups, participation in this study will not impact use of 
these modalities. We do not anticipate the study groups to differ significantly in their use 
of medical therapies, though these factors will serve as control variables in the final 
analyses as necessary. 
 
After completion of the final study follow-up, patients randomized to receive usual care 
will be offered the study intervention materials to be delivered either in person, via mail 
or email. They will also be offered the opportunity to meet with a study clinician in person, 
by phone, or via secure video to review the materials and ask questions. At the time of 

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enrollment, patients will be made aware that these resources will be available upon 
completion of the final study assessment. 
 
5.4 Data Collection Procedures 
 
5.4.1 Timing of Data Collection 
The following table depicts the assessments, measures and time points for the proposed 
data collection. 
 
Screening 
Baseline 
Weeks 8, 
16, 24 
Post 
Study 
Chart review for eligibility and baseline clinical 
characteristics 
X 
Modified Medical Research Council Dyspnea Scale 
(MMRCDS) 
X 
X 
X 
Cancer Dyspnoea Scale (CDS) 
X 
X 
Demographic Questionnaire 
X 
Functional Assessment of Cancer Therapy-Lung 
(FACT-L) 
X 
X 
Hospital Anxiety and Depression Scale (HADS) 
X 
X 
Godin-Shephard Leisure Time Physical Activity 
Questionnaire (GSLTPAQ) 
X 
X 
Chronic Respiratory Disease Questionnaire (CRQ) 
X 
X 
Self-report ECOG Performance Status 
X 
X 
Actigraph and activity log (for 3 days) 
X 
X (week 
8 only) 
Chart review for treatment, medical orders, service 
utilization 
X 
 
5.4.2 Data from the Electronic Health Record 
Clinical information regarding tumor type (NSCLC, SCLC, mesothelioma), date of 
diagnosis of advanced disease, previous cancer therapies, current treatment regimen, and 
performance status will be collected at baseline. The post study review of the electronic 
health record (EHR) will include information on disease progression, any changes in 
cancer treatment, and number of emergency department (ED) visits and hospitalizations 
during the study period. 
 
Medical comorbidity will be assessed at the time of baseline data collection with the 
Charlson Comorbidity Index (CCI).67 We will review health records for the presence of 
(1) pulmonary, cardiac, hepatic, and renal disease, (2) current and other malignancies, 
and (3) other morbidities (diabetes, cerebrovascular disease, and rheumatologic 
conditions) and assign the appropriate CCI score. 
 
Medical orders: We will collect data on medications to alleviate dyspnea (e.g., opioid 
analgesics), supplemental oxygen, and procedures for managing pleural effusions or 
bronchial obstruction. 
 
Dr. Temel (Co-I), a thoracic oncologist, will oversee the collection of clinical information 
from the EHR as well as the review of medical scans to determine whether participants’ 

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disease progressed during the study period. 
 
5.4.3 Data Storage 
Study source documents, including but not limited to signed informed consent forms, 
completed eligibility checklists, and participant questionnaires, will remain confidential 
and be scanned and stored on secure Partners computers and in REDCap. Since these 
records necessarily contain patient identifiers, only study staff will have access to them. 
 
Study staff will scan completed source documents, which may include identifiers such as 
participant names, upon their completion. Location, time, and date of the scanning of the 
document will be recorded. After the source document is scanned and the corresponding 
electronic document is confirmed to be legible, it will be collected and destroyed 
immediately. Study staff will destroy the original copy of the source document by 
following MGH procedures of destroying documents with Personal Health Information 
(PHI). 
 
If a patient requests to view his or her data collected by the actiwatches (activity, mobility 
and sleep statistics), study staff can provide patients with this data. Identifiers such as name 
will only be used during the initial data retrieval process and can be destroyed once all data 
records have been obtained and data analysis completed. Data abstracted from the 
electronic health record in Section 5.4.2 will be maintained in REDCap. REDCap 
(Research Electronic Data Capture) is a free, secure, HIPAA-compliant web-based 
application hosted by the Partners HealthCare Research Computing, Enterprise Research 
Infrastructure & Services (ERIS) group. Vanderbilt University, with collaboration from a 
consortium of academic and non-profit institutional partners, has developed this software 
toolset and workflow methodology for electronic collection and management of research 
and clinical study data. Data collection projects rely on a study-specific data dictionary 
defined by members of the study staff with planning assistance from Harvard Catalyst | 
The Harvard Clinical and Translational Science Center EDC Support Staff. The iterative 
development and testing process results in a well-planned data collection strategy for 
individual studies. REDCap provides flexible features that can be used for a variety of 
research projects and provides an intuitive interface to enter data with real time validation 
(automated data type and range checks). The system offers easy data manipulation with 
audit trails, reports for monitoring and querying participant records, and an automated 
export mechanism to common statistical packages (SPSS, SAS, Stata, R/S-Plus). 
 
5.5 Description of Study Processes 
The following tables provide an overview of the study timeline and the timing of recruitment, 
enrollment, and participant contact. 
 
Time Point 
Study Procedure 
Months 0-3 
Study Staff Training: 
• 
Hire and train oncology nurses in content and delivery of the brief behavioral 
intervention for dyspnea 
• 
Hire and train 2 research assistants in study procedures, recruitment, enrollment, 
data collection, etc. 

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Months 4-54 
Randomized Controlled Trial: 
• 
Enroll and randomly assign 220 patients (110 per study group) to receive either 
the brief behavioral intervention for dyspnea or usual care across study sites (i.e., 
MGH Cancer Center, DFCI, Mass General Cancer Center at Newton-Wellesley 
Hospital, and Mass General/North Shore Cancer Center-Danvers) 
• 
Complete 8,16, 24-week post assessments and data extraction from the electronic 
health record 
Months 55-60 
Analysis and Submission of Follow-up Grant Proposal: 
• 
Complete data analyses and submit primary manuscripts 
• 
Prepare and submit grant proposal for large-scale multisite dissemination and 
implementation study 
 
Point of Contact 
Timing 
Study Procedures 
Initial screen and 
consent 
Upon clinician 
approval 
▪ Screen in outpatient clinic, infusion suite or via 
telephone 
▪ Patients will self-report shortness of breath (using 
the MMRCDS) 
▪ If MMRCDS score ≥2, study staff will obtain 
informed consent and email oncology 
clinician to notify that the patient screened 
positive for dyspnea 
▪ If MMRCDS score <2, study staff will screen 
patient again in 3 months 
Enrollment 
- Baseline self- 
report assessment 
Upon confirmation 
of prescreen 
eligibility 
▪ Participant completes self-report battery of 
questionnaires 
▪ Provide patient with wrist actigraph and activity 
log with instructions to wear for the 3 days 
following the baseline assessment. 
▪ After 3 days, study staff calls and informs patient 
of randomization and schedules session one for 
intervention participants. 
▪ Participant returns actigraph watch and activity 
log in-person or mails it back to study staff. 
Randomization 
notification 

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Session One (if 
randomized to 
dyspnea 
intervention group) 
Within 6 weeks of 
enrollment and 
baseline data 
collection 
▪ Nurse interventionist delivers Session One either 
in clinic or virtually by phone or secure video 
▪ Study staff will contact participant to schedule 
Session Two 
Session Two (if 
randomized to 
dyspnea intervention 
group) 
After session 1, 
within 8 weeks of 
enrollment 
▪ Nurse interventionist delivers Session Two either 
in clinic or virtually by phone or secure video 
Follow-up – Week 8 
Assessment 
8 weeks after 
baseline data 
collection 
▪ Participant completes follow-up questionnaires 
either in person while in clinic or remotely via 
mail, REDCap email, or telephone. 
▪ Study staff instructs participant to wear actigraph 
and log activity for the 3 days following the 
completion of their week 8 self-report 
assessments. Study staff collects actigraph and 
activity log from participant via mail. 
▪ For the procedures listed above, the study staff 
member delivering the assessment will remind 
the patient not to inform them of whether they 
received the intervention for breathlessness. 
Follow-up – Week 16 
and 24 Assessments 
16 and 24 weeks 
after baseline data 
collection 
▪ Participant completes follow-up questionnaires 
either in person while in clinic or remotely via 
mail, REDCap email, or telephone. 
▪ For the procedures listed above, the study staff 
member delivering the assessment will remind 
the patient not to inform them of whether they 
received the intervention for breathlessness. 
 
5.5.1 Instrument Administration 
A study staff member blind to group assignment will administer study assessments at 
baseline and multiple follow-up time points (at weeks 8, 16, and 24) with a +/- 2 week 
window to accommodate patient schedules. The assessment battery takes approximately 
30 minutes to complete. The baseline and follow up assessments (at 8, 16, and 24 weeks) 
will occur either in clinic, by mail, telephone or online via REDCap. We selected the six- 
month time frame for follow-up assessment to evaluate the long-term impact of the 
intervention on patient outcomes while recognizing the limited life expectancy of patients 
with advanced lung cancer. The self-report measures have strong psychometric properties 
and been well validated in previous studies. 
 
If a participant expresses that he or she is not willing or able to complete the self-report 
packet in full, the study staff will offer an abbreviated version containing the primary 
outcome assessments (MMRCDS, CDS, HADS, and FACT-L). This short form will only 
be offered if a patient initially refuses to complete the entire questionnaire packet. Each 
participant will receive the actigraph at enrollment and will be instructed to wear the 
watch for the 3 days following their baseline assessment. In preparation for Week 8 follow- 
up, participants will receive the wrist actigraph either in person in clinic or by mail. 

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Patients will be instructed to wear the actigraph device for the 3 days following the 
completion of their 8-week self-report assessment. After this 3-day period, study staff will 
arrange a FedEx pick-up to retrieve the actigraph device. 
 
If a patient passes away while in possession of an actigraph, we will call the person 
identified as a contact in the Participant Locator Form to offer our condolences. We will 
also explain that we will send a prepaid envelope to them addressed to our study staff, 
and instruct them to place the actigraph in the envelope, seal it, and send the envelope 
back to us in the mail (USPS). If we cannot reach the patient’s contact by phone, we will 
send the prepaid envelope along with a note offering our condolences and instructions on 
how to return the actigraph. 
 
We will call the patient’s contact person up to three times, allowing for at least three 
business days between each phone call if we cannot reach the contact person. At the time 
of enrollment, we inform the patient that the contact person is someone who we will call 
if the patient is unreachable. The participant typically lists his/her designated primary 
caregiver or spouse, who usually lives with the patient. On the rare occasion that this 
person does not live with the patient, we will work with the contact person to problem- 
solve how to reach out to someone who lived with the patient or has access to the 
residence in order to retrieve the actigraph and mail it back to the study staff in the 
prepaid envelope. If it is not possible, then we will consider the data to be lost. We do not 
anticipate this to be a frequent occurrence. 
 
5.5.2 Intervention Administration 
Patients assigned to the brief behavioral intervention for dyspnea will participate in two 
sessions. The first session will occur at the patients’ next scheduled clinic visit (either in 
the infusion suite or the outpatient clinic) via telephone, or via secure video following 
baseline data collection. The first session must occur within six weeks of the baseline data 
collection. Chemotherapy regimens for patients with advanced lung cancer are typically 
administered every two to three weeks. Thus, the six-week window will allow all enrolled 
patients to have a scheduled appointment, with additional time should their treatment be 
delayed for any reason (e.g., holidays or low blood counts). In the unlikely event that the 
patient is unable to come to the hospital for the first intervention session before the six- 
week window closes, the patient will be mailed the necessary study materials and receive 
the first session over the telephone or via secure video to remain in window. In the rare 
cases that the patient is still unable to complete the first session before the six-week window 
closes, the patient will be re-administered their baseline assessments either at their next 
appointment or by mail, telephone, or online via REDCap. Study procedures will reset from 
the new baseline assessment. 
 
The second session will occur at the patient’s subsequent clinic visit, over the telephone, 
or via secure video, within eight weeks of the baseline data collection. 
 
Participants in both arms of the study will receive usual care for their dyspnea under the 
care of their clinicians. 

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5.5.3 Special Concerns 
 
Breach of confidentiality is a concern in all studies with human subjects. Patient 
participants will be completing self-report assessments; thus safeguards will be put in place 
to ensure that participant information is kept private and confidential. All electronic data 
will be stored in password-protected computer files and online databases (i.e. REDCap), 
accessible only to trained study staff. Participants’ data will be identified by an ID number 
only, and a link between names and ID numbers will be kept in a separate password- 
protected computer file. Data will not be shared with individuals other than study staff. 
 
5.5.4 Compensation 
Study participants will not receive compensation for participating in this study or for 
completing questionnaires. 
 
5.6 Adverse Reactions and Their Management 
 
5.6.1 Reporting Adverse or Unanticipated Events 
Identification of adverse events may come through notification from the study participant, 
caregiver, clinician, or from review of the electronic health record. In such circumstances, 
the PIs and investigative team will follow the following procedures: 
a. Serious Adverse Events. Given that this study is a randomized trial comparing a brief 
behavioral intervention compared to a usual care control group, we do not anticipate any 
study-related events meeting the FDA definition of a SAE (i.e., any fatal event, 
immediately life-threatening event, permanently or substantially disabling event, event 
requiring or prolonging inpatient hospitalization, or any congenital anomaly). The 
proposed study population is comprised of individuals diagnosed with advanced lung 
cancer who frequently experience disease worsening, high rate of symptoms, and 
hospitalizations from the underlying disease and/or side effects of treatment. Therefore, as 
advanced lung cancer is a chronic-type terminal illness, regular fluctuations in cancer- 
related symptoms, disease worsening, hospitalizations, emergency department visits, and 
deaths are to be expected throughout the study, and we will not consider or report such 
events as SAEs in this trial. 
b. Non-Serious Adverse Events. The IRB will be provided with unblinded summaries of study 
related non-serious adverse events by treatment group at the continuing reviews. These 
reports will include types of events, severity, and treatment phase. To date, the majority of 
non-serious adverse events in our prior supportive care studies have been due to patient 
discomfort with the study questionnaires. 
 
5.6.2 Anticipated Reactions 
As this is a behavioral study, there are no ingested medications, and no biomedical 
procedures. It is unlikely that participants will be at any risk for physical harm as a result 
of study participation. 
 
Participants may find some of the questions asked in the questionnaire to be emotionally 
upsetting, and may experience some fatigue from the length of the assessment battery. As 
this is a study targeting symptoms that are debilitating and interfere with quality of life, it 
is possible that some participants will experience depression and one of the major 
symptoms of depression, suicidality. 

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Participants may also find some of the breathing exercises from the dyspnea intervention 
uncomfortable during sessions and during home practice. 
 
5.6.3 Reaction Management 
Following the explanations by the study staff, participants will either sign a detailed 
consent form or provide verbal consent. The consent process will include all of the study 
procedures, information about potential risks and benefits of participation, and information 
regarding whom the participant can contact for further questions. It also will state that 
participation is voluntary, that participants can refuse to answer any question, that they can 
withdraw from the study at any time, and that study participation is in no way related to 
their medical care. The PI will review all informed consents within one week of their 
completion. All study staff will complete the required human subjects training before they 
are allowed to work on any human subject aspects of the study. 
 
The need for further intervention and referral regarding anxiety and depression symptoms 
will be determined by clinical cutoffs on the subscales of the Hospital Anxiety & 
Depression Scale (HADS) and by clinical assessment of the trained study nurse should any 
participant note heightened emotional distress and/or suicidality. Both the anxiety and 
depression subscales scores of the HADS range from 0 to 21, with a score of 11 or greater 
indicating definitive anxiety or depression. A score of less than 7 is considered normal, and 
a score of 8-10 on each subscale suggests probable anxiety and depression. Study patients 
whose scores increase from the normal or probably range to the more severe range for 
depression (i.e., > 11) will be called by qualified study staff (e.g., Dr. Greer, a licensed 
clinical psychologist, or similarly trained designee) to determine if the patient requires 
further intervention for his or her mood symptoms. Study staff will also assess for any 
suicidal ideation and ensure that the patient is not at any risk for self-harm. If the patient 
needs further outpatient services for depression, including pharmacotherapy, or is at risk 
for self-harm requiring hospitalization, study staff will make the necessary referrals for 
treatment. For example, for patients who are distressed but in no danger to self or others, 
study staff will refer either to the MGH Oncology Social Work Service or to the MGH 
Ambulatory Psychiatric Services (617-724-5600), including the Cognitive-Behavioral 
Therapy Program. If suicidality or risk of harm to others is otherwise discovered at any 
study visit, the participant will be referred to appropriate services. Specifically, in the case 
that hospitalization is required, study staff will contact and escort the patient to the MGH 
Acute Psychiatry Service (617-726-2995), with the aid of the MGH Police & Security if 
necessary (617-726-2121). Study staff assessments of patient distress and/or risk will be 
documented in the electronic medical record so that the clinical team is notified of any 
potential need for increased support. 
 
If participants find the dyspnea intervention uncomfortable and/or upsetting during 
intervention sessions or during home practice, the participants or the study interventionists 
delivering the intervention may page the PI (Dr. Greer) at any time. Dr. Greer is a licensed 
clinical psychologist with extensive experience delivering cognitive behavioral treatments 
for individuals with advanced lung cancer (see previous clinical studies). 
 
The PI, co-investigator team, and the nurse study interventionists will meet at least monthly 
to review study progress, ensure proper implementation of the intervention, and review any 
adverse reactions that occur. The PI and the study staff for this study will also meet weekly 
to review consents and collected data to ensure proper adherence to study protocol. 

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6.0 STATISTICAL ANALYSIS 
 
6.1 Study Endpoints 
 
6.1.1 Primary and Secondary Endpoints 
The primary outcome is comparison of the MMRCDS and CDS severity scores at 8-week 
post-assessment between study arms, controlling for baseline values. 
 
The secondary outcomes will be comparison of quality of life, anxiety, depression, and 
activity level between study groups. To assess quality of life, we will compare the post- 
assessment (8-week) FACT-L scores between study arms, controlling for baseline values. 
To evaluate anxiety and depression symptoms, we will similarly compare the continuous 
scores as well as rates of depression and anxiety symptoms reported per HADS score at 8 
weeks between study arms, controlling for baseline values. To assess activity level, we 
will compare the percentage of time spent immobile but awake on actigraphy and self- 
report weekly leisure-time physical activity score at 8 weeks between study groups, 
controlling for baseline values. 
 
6.2 Sample Size and Power Calculation 
Although we observed a large effect size for the brief behavioral intervention on patient-reported 
dyspnea in our previous trial (Cohen’s d=1.0), we chose to be conservative in estimating the sample 
size to power the proposed RCT given the inclusion of usual care control group, proposed tests of 
mediation and moderation, and rate of attrition observed in our pilot trial (i.e., 16%). Therefore, if 
a total of 200 study participants complete this two-treatment parallel-design study, the probability 
is 80% that the study will detect a treatment difference in the primary and secondary outcomes at 
a two-sided 0.05 significance level (if the true difference between treatments is 0.40 times the 
standard deviation (i.e., the lower bound of a medium effect size). 
 
6.3 Analysis Plan 
 
6.3.1 Aim 1 
Aim 1: To demonstrate the efficacy of the brief behavioral intervention for improving 
dyspnea (primary outcome) in patients with advanced lung cancer. 
Hypothesis 1: Participants with advanced lung cancer who are randomly assigned to 
receive the brief behavioral intervention will report statistically and clinically significant 
improvements in dyspnea (per self-report MMRCDS and CDS) compared to those 
assigned to usual care. 
Analysis: Analyses will begin with descriptive and graphical summaries of the endpoints. 
As the MMRCDS is an ordinal measure, the statistical significance of between-group 
differences in the primary outcome will be assessed first with the Wilcoxon-Rank Sum test 
and then with generalized estimating equations (GEE), with appropriate covariates. The 
CDS is a continuous interval measure, and we will assess between-group differences in 
these scores using general linear models (GLM). All statistical tests will be two-sided with 
an alpha level of .05. For these primary outcomes, we will examine between-group 
differences (i.e., intervention versus control) in MMRCDS and CDS scores at the 8-week 
post-assessment, controlling for baseline values. In the event that the effect of the 
intervention differs by cancer type, use of opiate medication or other patient characteristic, 
we will examine these variables as interaction terms in the GEE and GLM analyses. We 
will also evaluate generalized linear mixed models of the longitudinal data, allowing us to 

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account for dependency among MMRCDS and CDS scores over time and to control for 
demographic and clinical factors, such as disease progression, (as necessary for any 
imbalances in baseline variables) when examining between-group differences in the 
MMRCDS and CDS scores across the multiple study time points (i.e., baseline, 8, 16, 24 
weeks). Finally, we will compute the effect sizes and Reliability Change Index68 to assess 
practical and clinical significance of the differences in the primary and secondary 
outcomes. The GLM model will generate an effect size estimate, which can also be 
calculated by hand (d=Mean change score CBT group - Mean change score control group/SD pooled). Cohen69 
utilizes cutoffs of 0.2 for a small effect, 0.5 a medium effect, and 0.8 for a large effect. 
 
6.3.2 Aim 2 
Aim 2: To demonstrate the efficacy of the brief behavioral intervention for improving 
quality of life, anxiety, depression, and activity level (secondary outcomes) in patients with 
advanced lung cancer. 
Hypothesis 2: Participants with advanced lung cancer who are randomly assigned to 
receive the brief behavioral intervention will experience statistically and clinically 
significant improvements in quality of life (FACT-L), anxiety and depression (HADS), as 
well as activity level (per self-report Godin-Shephard Leisure-Time Physical Activity 
Questionnaire and the percentage of time spent immobile but awake on actigraphy) 
compared to those assigned to usual care. 
Analyses: The statistical significance of between-group differences for the continuous 
secondary outcomes will be assessed with general linear models (GLM) and linear mixed 
models, with appropriate covariates and an alpha level of .05. We will examine the 
between-group differences (i.e., intervention versus control) at 8-week post-assessment for 
each specific secondary outcome (all are continuous variables), controlling for baseline 
values. In the event that the effect of the intervention differs by cancer type, use of opiate 
medication or other patient characteristic, we will examine these variables as interaction 
terms in the GLM analysis. We will explore independent improvements in these secondary 
outcomes by adding changes in MMRCDS or CDS severity scores as a covariate. Finally, 
we will also again estimate practical and clinical significance of these outcomes (using 
Cohen’s d and Reliability Change Index) and conduct linear mixed models to examine the 
trajectory of between-group differences in these variables across all study time points. 
 
6.3.3 Aim 3 
Aim 3: To explore mediators and moderators of the effect of the brief behavioral 
intervention on patient-reported outcomes. 
Hypothesis 3: Intervention effects on patient-reported dyspnea will be mediated by 
improved mastery in managing breathlessness and potentially moderated by patient 
demographic and clinical factors (e.g., gender, age, opioid use, performance status, and 
disease comorbidity). 
Analyses: We will conduct bootstrapped tests of mediation to determine whether group 
differences in self-reported dyspnea (outcomes: MMRCDS and CDS) are mediated by 
improved mastery in managing the symptom (mediator: CRQ). Finally, we will create 
interaction terms for the GEE analyses and linear mixed models to examine whether 
differences in reported dyspnea are moderated by patient factors (e.g., gender, age, opioid 
use, etc.). 
 
6.3.4 Exploratory Analyses of Service Utilization 
Although we likely will not have sufficient power to examine statistically the intervention 
effects on service utilization, we will at a minimum calculate descriptive statistics on 

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rates of ED visits and hospitalizations by study group. Otherwise, if possible, we will 
conduct Fisher’s exact tests and logistic regression to explore differences in rates of ED 
visits and hospitalizations between groups, controlling for any confounders as needed. 
 
6.4 Handling of Missing Data 
The analyses will initially focus on the study completers to estimate the effect of the brief 
behavioral intervention in patients with advanced lung cancer who completed the protocol as 
intended without imposing assumptions about missing data. We will also use the intention-to-treat 
principle with all randomized subjects, conducting sensitivity analyses to explore how various 
assumptions about missing data and differences between completers and non-completers affect the 
estimated outcomes. If data appear to be missing at random, we will employ multiple imputation 
methods. However, if we find that patients do not complete the study because of disease worsening, 
suggesting missing data are not random, we will employ maximum likelihood estimation from 
incomplete data, under the direction of our biostatistician, Ms. Muzikansky. 
 
6.5 Potential Problems, Alternative Strategies and Benchmarks for Success 
The potential problems and alternative strategies that we considered in developing this study 
proposal pertain to the selection of interventionists, length of treatment, and nature of the control 
group. Specifically, we recognize that patients with advanced lung cancer may benefit from 
meeting with clinical psychologists and/or social workers with trained expertise in behavioral 
medicine. Although increasing contact with such clinicians may enhance the robustness of the 
intervention, we are responding to the present challenges that exist in meeting the psychosocial and 
symptom management needs of patients with cancer. Access to supportive care for oncology 
patients is limited not only by the inadequate number of mental health and palliative care providers, 
but also by insufficient training of existing clinicians with respect to empirically-supported 
techniques, such as cognitive-behavioral approaches.43 In our national survey of community 
oncologists, a majority reported that they lack access to mental health providers for referrals.70,71 
We therefore decided to administer the point-of-care dyspnea intervention, delivered by trained 
oncology nurses, as we observed that this approach was feasible and preferable to patients with 
advanced lung cancer. Similarly, prior studies of comprehensive dyspnea management 
interventions include numerous visits with multiple medical providers across several months.37,46 
Given the disease burden of the patient populations in the proposed study, we chose to keep the 
intervention brief, delivered in tandem with existing outpatient appointments. Despite this short- 
time frame of the targeted behavioral intervention, we nonetheless observed a large effect size for 
self-reported dyspnea over time in our pilot study.23 Interventions that can be integrated within the 
flow of care that are minimally resource intensive yet effective have greater potential for broad 
adoption and implementation across diverse cancer care settings. Finally, we elected to conduct a 
RCT with a usual care control group rather than employ alternate experimental methods, such as a 
wait-list crossover or staggered treatment design, because of the shortened life expectancy of the 
study population. We also considered, but ultimately did not include, an attention-matched control 
group given the lack of an alternative, evidence-based psychosocial comparator as well as potential 
ethical considerations of asking patients with advanced disease to meet with a clinician for some 
sort of “sham” treatment. Moreover, no data suggest that attention alone would influence dyspnea. 
Otherwise, we will not limit access to usual care but rather examine the effects of the behavioral 
intervention above and beyond usual care. 
 
Benchmarks for success in the proposed study will not simply include a replication of our 
successful pilot study showing significant effects of the brief behavioral intervention on dyspnea 
management. We also aim to increase the generalizability and reach of the intervention by training 
oncology nurses and including a second study site. Also, we will consider clinically meaningful 

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improvements in quality of life (i.e., >5 point change on FACT-L) and a Reliability Change 
Index>1.96 for the outcomes as other markers for success. If we do not achieve these benchmarks, 
we will utilize qualitative methods to gather feedback from the relevant stakeholders (i.e., patients, 
nurse interventionists, etc.) to ascertain ways to modify the intervention content and/or delivery in 
order to maximize its effectiveness and adoption in multiple cancer care settings. 

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