Clinical trial NCT01902966
Conditions: Cervical Cancer
Keywords: Cervical Cancer Propranolol Betachron Inderal Beta blocker Questionnaires Surveys Symptom inventory Anxiety and depression survey Pain inventory Quality of life survey Relaxation audio recording MP3 player Diary
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-09-11; Completion date: 2020-08-14
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn how many patients with advanced, recurrent, incurable cervical cancer will complete questionnaires about symptoms, any anxiety, depression, and/or pain, and the quality of their lives. Researchers also want to learn how many of these patients will complete a study treatment of propranolol hydrochloride and relaxation and guided imagery sessions.

Researchers also want to learn if and how propranolol hydrochloride and relaxation and guided imagery may affect cancer symptoms and any anxiety, depression, and/or pain, and quality of life.

Propranolol hydrochloride is designed to block certain chemicals that affect the heart.

Relaxation and guided imagery sessions are a form of relaxing meditation that involves tensing and relaxing various parts of your body from your feet to your head. In the guided imagery portion, you listen to recordings that are designed to help with calmness, control, and decreasing stress.

Detailed description:
Study Therapy Administration:

If you are found to be eligible to take part in this study, you will take propranolol by mouth 2 times a day.

While taking the drug, you should continue to check your blood pressure daily with your own personal blood pressure machine, at your local pharmacy, or in the clinic. If you are personally monitoring your blood pressure, you should contact the research nurse if the systolic blood pressure (SBP - the higher number) is less than 110, or if the diastolic (DBP - the lower number) is less than 50 (or your heart rate is 50-60 and you show symptoms at 2 different timepoints 24 hours apart). The study doctor may decide to lower or raise your dose of study drug during the study based on your heart rate and/or blood pressure measurements.

You will fill out a pill diary to write down the doses of propranolol that you take each day.

For the relaxation and guided imagery sessions, you will be given an MP3 player with an audio recording that you should listen to 2 times a week for up to 4 months (or longer if you choose). The study staff will talk to you about how to complete the sessions. You will fill out a relaxation diary to write down whether you were able to complete the sessions and whether you had any difficulties with it, such as distractions.

You should bring both diaries to the clinic at each visit.

Study Visits:

At Month 1:

* Your vital signs will be measured.
* You will be asked about any side effects you may have had.

At Months 2 and 4:

* Your vital signs will be measured.
* You will be asked about any side effects you may have had. Blood (about 5-6 teaspoons) will be drawn for routine tests and for testing on cytokines, RNA, and tumor markers.
* You will complete the same questionnaires as at screening.
* If the doctor thinks it is needed, you will have an EKG to check your heart function.
* If you are an MD Anderson participant, the test to find out how many calories you need to have on a daily basis will be repeated.
* At Month 2 only, if the doctor thinks it is needed, you will have a CT scan of the chest, abdomen, and pelvis to check the status of the disease.
* At Month 4 only, any updates to your medical history will be recorded. You will have a physical exam.

Length of Treatment:

You may continue the study therapy for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study therapy if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your active participation on the study will be over after the last visit. The study staff will continue checking your medical record from then on to see how you are doing.

This is an investigational study. Propranolol is FDA approved and commercially available to treat certain heart and blood pressure problems, anxiety, migraines, and tremors. Its use in this study is investigational.

Up to 20 participants will be enrolled in this multicenter study. Up to 5 will be enrolled at the Harris Health System. Up to 10 will be enrolled at MD Anderson.

Arms: arm 1: A starting dose of propranolol 20 mg is taken by mouth twice a day (40 mg/day). If patient tolerates the initial dose (no hypotension or bradycardia), dose increased to 40 mg by mouth twice a day at start of second month of therapy. Patients record study medication taken each day in a pill diary. Patient given an MP3 player with an audio recording to listen to 2 times a week for up to 4 months. The recording lasts 20 minutes. Relaxation diary completed stating whether patient was able to complete the sessions and whether they had any difficulties with it. Questionnaires completed at baseline, 2 months, and 4 months.
Interventions: intervention 1: Propranolol intervention 2: Diary intervention 3: Relaxation Audio Recording intervention 4: Questionnaires
Intervention descriptions: intervention 1: Starting dose: 20 mg is taken by mouth twice a day (40 mg/day). intervention 2: Patients record study medication taken each day in a pill diary. Relaxation diary completed after listening to audio sessions twice a week. intervention 3: Patient given an MP3 player with an audio recording to listen to 2 times a week for up to 4 months. The recording lasts 20 minutes. intervention 4: Questionnaires completed at baseline, 2 months, and 4 months.

Protocol documents:
Prot_SAP_000.pdf: 
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Effect of a Beta Adrenergic Blockade combined with Relaxation/Guided Imagery 
Audio Intervention on symptom distress in Women with Advanced, Recurrent 
Incurable Cervical Cancer-Feasibility study
Principal Investigator:
Lois M Ramondetta, M.D.
Division of Gynecologic Oncology
and Reproductive Medicine
MD Anderson Cancer Center
Houston Texas 77030
Telephone: (713) 745-0307
Email: lramonde@mdanderson.org
Co-Investigators:
MD Anderson Cancer Center
Anil Sood, MD
Marieberta Vidal, MD
Robert Coleman, MD
Lorenzo Cohen
Charlotte Sun, PhD
Ronny Dev, MD
Statistician:
Diana Urbauer MS
The Harris Health System 
Jeanette Ferrer, DO


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SCHEMA
Blood drawn prior to administration of Propranolol after consented for study
Fill out questionnaires
Instruct on use of R/GI MP3 use and diary
Propranolol 20mg po bid initiated
Patient instructed to listen to MP3 2x a week and record in diary
Increase propranolol to 40 mg po bid if the patient is tolerating at one month time point.
Continue oral Propranolol until removal from study
Blood drawn and completion of questionnaires after the completion of every two cycles (2 
mos and 4 mos)


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TABLE OF CONTENTS
1.0
OBJECTIVES
2.0
BACKGROUND AND RATIONALE
3.0
PATIENT ELIGIBILITY 
4.0
STUDY MODALITIES
5.0
PROPOSED TREATMENT/STUDY PLAN
6.0
SAFETY PLAN AND CRITERIA FOR REMOVAL FROM STUDY
7.0
TREATMENT MODIFICATIONS
8.0
STUDY PARAMETERS AND SERIAL OBSERVATIONS
9.0
EVALUATION CRITERIA
10.0
DURATION OF STUDY
11.0
STUDY MONITORING AND REPORTING PROCEDURES
12.0
STATISTICAL CONSIDERATIONS
13.0
DATA MANAGEMENT
14.0
TRANSLATIONAL RESEARCH
15.0
PROTOCOL COMPLIANCE
16.0
REFERENCES
APPENDIX A
- Prioritization List
APPENDIX B
- Protocol Checklist
APPENDIX C
- ZUBROD Performance Status Scale
APPENDIX D
- M. D. Anderson Symptom Inventory (MDASI) Core Items – English
APPENDIX E
- M. D. Anderson Symptom Inventory (MDASI) Core Items - Spanish
APPENDIX F
- Hospital Anxiety and Depression Scale (HADS) – English
APPENDIX G
- Hospital Anxiety and Depression Scale (HADS) – Spanish
APPENDIX H
- Procedure for Submission of Blood Specimens
APPENDIX I
- Brief Pain Inventory (BPI) – English
APPENDIX J
- Brief Pain Inventory (BPI) - Spanish
APPENDIX K
- FACT-Cx - English


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APPENDIX L
- FACT-Cx – Spanish
APPENDIX M
- Pill Diary – English
APPENDIX N
- Pill Diary – Spanish
APPENDIX O
- Common Side Effects of Beta Blockers – English
APPENDIX P
- Common Side Effects of Beta Blockers - Spanish
APPENDIX Q
- Relaxation Practice Log – English
APPENDIX R
- Relaxation Practice Log - Spanish
APPENDIX S
- MP3 Player Instructions – English
APPENDIX T
- MP3 Player Instructions – Spanish
APPENDIX U
- FACT-Cx Scoring Guidelines


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1.0
OBJECTIVES
1.1
Primary Objectives:
1.1.1
To determine the proportion of patients completing symptom inventory, 
anxiety and depression survey, pain inventory, and quality of life 
surveys (MDASI, HADS, BPI, FACT-Cx).
1.1.2
To determine the proportion of patients completing combined intervention 
of twice daily beta blocker use and twice weekly relaxation and guided 
imagery (R/GI) at two time points (2 mos and 4 mos).
1.2
Secondary Objectives:
1.2.1
To index cervix cancer specific symptomatology in this population and the 
serial change over intervention.
1.2.2
To determine the impact of beta blocker and R/GI on symptoms, anxiety 
and depression, pain, and quality of life (MDASI, HADS, BPI, FACT-Cx)
1.3
Exploratory objectives
1.3.1
To measure changes in serum levels of IL-6, IL-8, IL-10 and VEGF, CRP 
during treatment with propranolol in addition to receiving PMR
intervention 
1.3.2
To measure changes in resting energy use during treatment with 
propranolol in addition to receiving PMR intervention 
1.3.3
To measure HPV components (e.g.E6 or E7 are reduced following 
treatment with beta blocker) in circulating cell-free DNA during 
intervention as a quantative assessment using qRT-PCR.
2.0
BACKGROUND AND RATIONALE
2.1
Women should not die of cervical cancer…but they do. Most cases of the 
disease are preventable, and it is highly curable if caught early. The primary cause 
of cervical cancer is HPV2. Furthermore, worldwide, cervical cancer is the second 
most common cause of cancer deaths in women [1]. In 2007, 12,280 women in 
the United States were diagnosed with cervical cancer, and more than 4000 died 
of it [1]. Furthermore, an estimated 530,000 cases of cervical cancer were 
diagnosed and 275,000 patients died of the disease in 2008, underscoring the 
tremendous loss of life attributable to cervical cancer [2].  Most importantly, 
chronic multidimensional pain is a prominent aspect of survival in cervical cancer 
patients [3-5]. The pain is often a combination of symptoms from direct pressure 


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from a mass, pain from nerve involvement of tumor or residual platinum induced 
neuropathy, pain from lymphedema and possibly from percutaneous nephropathy 
tubes.
Very few, if any, reports in the literature suggest that long-term complete clinical 
remission is possible in patients with advanced, recurrent, or metastatic cervical 
cancer [6-8]. Moreover, in all of the patients in these studies, if a complete 
response occurred, it did so during the first use of chemotherapy for recurrence. 
The use of second- and third-line therapy in such patients invokes the concept of 
“do no harm.”  In other words, if use of these therapies has no chance of 
improving survival and possibly no chance of even increasing overall QOL, then 
why continue to administer them? Possible explanations are that writing a 
prescription may be easier than facing the realities of this tragic situation and 
some physicians may themselves have a false hope of prolonging life. More 
likely, this treatment originates from a deep desire to help but with a dearth of 
effective tools to do so.
Although few can argue that chemotherapy is beneficial when used to sensitize 
cervical cancers to irradiation, chemotherapy for cervical cancer outside of this 
use is controversial. Despite some improvements in response rates and duration of 
progression-free survival, only the combination of cisplatin and topotecan has 
been associated with prolongation of OS; specifically, use of this combination 
resulted in a median OS duration of 9.4 months compared with 6.5 months in 
patients who received cisplatin only (p = .017)[9, 10]. Unfortunately, with 
increased use of cisplatin for radiation sensitization, more recurrent cervical 
cancers seem to be resistant to cisplatin [10, 11]. For example, the overall 
response rate in patients in GOG 179 who previously received cisplatin for 
irradiation sensitization was 13% compared with 27% who had not [9, 11].
The Gynecologic Oncology Group (GOG)-204 protocol compared the four most 
effective chemotherapy doublets in treatment of recurrent cervical cancer in 
patients with no prior treatment of recurrences. The response rates ranged from 
23% to 29% [10]. No patients in the GOG-179 or -204 study experienced cures 
despite having slight increases in their PFS.  In these studies, although QOL was 
unaffected by the doublet used, no detailed assessment was done that addressed 
any of the components of QOL, including physical, psychological, social, and 
spiritual QOL. Furthermore, there has yet to be a trial for women with recurrent 
cervical cancer involving a “no chemotherapy/best supportive care” arm.  
Some anti-angiogenic targeted therapies for cervical cancer have demonstrated 
clinical response rates in heavily pretreated cervical cancer patients (10-34%) [12,
13].  Unfortunately, the majority of tested targeted agents, including cetuximab 
and single agent premetrexed (alimta) (13.9% RR and SD stable disease 53%), 
and erlotinib had little to no significant response and in some cases were 
associated with significant side effects.  For expensive agents such as 


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bevacizumab, until significant improvement in PFS and OS is demonstrated, their 
use will most likely be restricted to clinical trials.
We know now that more than 70% of incurable cancer patients believe their 
cancer is curable when receiving chemotherapy and that these beliefs prevent 
patients from entering into hospice/palliative care  [14]. This is unfortunate, as we 
have since learned from Temel and colleagues, who explored the benefits of early 
palliative (supportive) care in patients with incurable metastatic non-small cell 
lung cancer, that early palliative care not only leads to improvements in QOL and 
mood but also improves survival. In their study, the median survival duration was 
11.6 months versus 8.9 months in those who received earlier palliative care 
interventions [15]. The reason for the survival improvements gained from early 
palliative care include the improvement of medical comorbidities, facilitation of 
the receipt of effective chemotherapy as well as avoidance of detrimental cancer 
treatments. Although little is known about women with cervical cancer, depressed 
cancer patients have been shown to have worse survival and that improvement in 
these symptoms, not specific to any treatment, has been associated with increased 
survival [16, 17]. Although early palliative care has also been associated with less 
depression but at this point, lessened depression does not appear to mediate the 
survival benefit gained [15, 18].
The goal of future therapeutic trial design is to develop and evaluate a less 
expensive and safer method of inhibiting angiogenesis in recurrent cervical 
tumors. During this search, we must balance the search for effective therapies 
with the potential for side effects that can negatively impact QOL. In fact, 
members of the GOG have suggested that new targeted agents perhaps should not 
even be evaluated in women unfortunate enough to have recurrent cervical cancer 
owing to its predicted dismal response rate, worsening of QOL in patients who 
have it, and the possibility that a promising therapeutic targeted agent may be 
dismissed as ineffective because of lack of effect response rate (personal 
communication). Although improved survival duration is the goal, supportive care 
and efforts to improve QOL with early triaging and relief of symptoms and 
psychosocial difficulties is now recognized as the most important goal for patients 
with incurable advanced cervical cancer [19].
2.2
Neuroendocrine Stress Response
Stress is a complex process consisting of environmental and psychosocial factors 
that initiate a cascade of information-processing pathways in both the peripheral 
and central nervous system [20, 21]. These stress pathways elicit the “fight-or-
flight” stress responses in the autonomic nervous system or “defeat/withdrawal” 
responses produced by the hypothalamic-pituitary-adrenal axis. Activation of 
these pathways prepares a person to endure a threat. However, under chronic 
stress, most organs are negatively affected by prolonged exposure to 
glucocorticoids and catecholamines resulting from the stress. Until recently, stress 
was known to increase the risk of cardiac disease and infection [22]. Now, an 


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increasingly clear finding is that chronic changes in neuroendocrine dynamics can 
alter various physiological processes, such as adhesion of tumor cells to the 
extracellular matrix, cancer cell migration and invasion, angiogenesis, and cell 
survival, all of which are critical to tumor biology and pathogenesis [23].
Although most of the data collection regarding the immunohistochemical 
expression stress receptors has been performed in breast and ovarian cancer 
tissue, supportive data suggest that the neuroendocrine stress response is 
important to other cancers, as well.
2.3
Psychosocial Factors and Cancer
Researchers have long suspected that psychosocial factors play significant roles in 
malignant progression [21]. Clinical and epidemiological studies have recognized 
that behavioral risk factors such as stress, chronic depression, and lack of social 
support are risk factors for the development and progression of cancer. Also, 
increasing evidence indicates that psychosocial interventions improve the QOL of 
cancer patients although the effects of these interventions remain controversial 
[24, 25]. Studies have inconsistently demonstrated a relationship between 
behavioral risk factors and cancer initiation. However, researchers are just 
beginning to characterize the molecular mechanisms by which behavior impacts 
tumor growth [20]. Recent laboratory work demonstrated that imposed behavioral 
stress results in increased levels of tissue catecholamines, an increased tumor 
burden, and an increasingly invasive pattern of ovarian, pancreatic, and colon 
cancer growth in orthotopic mouse models of these cancers [23, 26-28]. These 
effects are mediated primarily by elevation of noradrenalin, adrenalin, cortisol, 
and vascular endothelial growth factor (VEGF) levels via E2-adrenergic receptor 
activation of the tumor cell cyclic AMP-protein kinase A signaling pathway [23,
26]. Supporting this finding, Lutgendorf and colleagues analyzed 10 ovarian 
carcinomas in patients with high depressive symptoms and low social support 
compared with patients at low levels of depressive symptoms and found increased 
activity of several E-adrenergically linked transcription control pathways, 
including the cyclic-AMP response element-binding protein/activating 
transcription factor and proinflammatory signal transducer and activator of 
transcription family of transcription factors [29], thereby confirming the 
importance of direct neuroendocrine regulation of tumor cell biology established 
in the in vivo orthotopic model [23]. Lutgendorf’s group also suggested that 
immune function can be preserved using integrative medicine/healing touch 
intervention with resultant preservation of natural killer (NK)-cell cytotoxicity 
[30]. Tumor response to treatment may also be affected by physiological stress, as 
stress hormones can interfere with chemotherapeutic efficacy and contribute to 
drug resistance [31] and may even be blocked by E2-adrenoceptor blockers [32].
2.4
Targeting stress and VEGF pathways to cancer?
Recently, interest in the role of adrenergic blockade in treatment of cancer has 
gained momentum. This attention originates from 1) studies demonstrating that 


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chronic stress results in physiological [21, 23, 33];  2) retrospective studies 
indicating that use of beta-blocking anti-hypertensives is associated with
improved survival and that the presence of adrenergic receptor beta (ADRB) 
correlates with prognostic indicators in certain cancer subtypes;  and 3) in vitro
and animal studies describing anticancer signaling activity, including reduction of 
serum and tumor VEGF levels with the use of beta adrenergic blocking agents 
[34-38]. In some cells, the effects of stress induced expression of angiogenic 
factors can be abrogated by beta-blockers. 
Retrospective data on cohorts of ovarian as well as breast cancer patients has 
suggested that the use of beta-blockers significantly reduces the risk of death.
Others have shown improved relapse-free survival intervals in patients with triple-
negative breast cancers and in patients with melanoma using beta-blockers 
Researchers have identified ADRB in breast, pancreatic, ovarian, lung, head and 
neck, prostate, and colon cancer cases 
Adrenergic blockade may affect survival in a number of ways
x
Decreasing angiogenesis via VEGF, MMMP (33)
x
Decreasing a prometastatic immune response (Il8) 
x
Decreasing adrenergic response [39, 40]
x
Decreasing symptoms such as cachexia [41]
To date, four studies of the use of beta-blockers for treatment of cancer in humans 
are under way. [http://www.clinicaltrials.gov]. 
2.5
Physiological and Psychological Stress and Cervical Cancer
Due to the association of low income and low levels of education, potential  
factors  that may contribute to psychosocial distress in women with cervical 
cancer include poor coping tools, depression, anxiety, lack of social support, drug 
use, comorbidities besides cancer (other chronic illnesses besides cancer), as well 
as having young children. Furthermore, but not yet fully explored in the cancer 
population, clinical trials of women diagnosed with cervical dysplasia suggest that 
guilt, self-neglect, and fear may contribute to overall psychosocial distress. These
issues are extremely relevant as clinical and epidemiological studies have now 
recognized that behavioral risk factors such as stress, chronic depression, and lack 
of social support are risk factors for the development and progression of cancer 
[21]. The impact of the stress response may be particularly relevant in cervical 
cancer patients because they may often present with greater disruptions of QOL 
than patients with other types of cancer[23, 33]. In fact, stress may play a strong 
role in the development of cervical dysplasia. This is extremely important to 
consider in the supportive care of women with cervical cancer as we begin to 
make further progress in our understanding of the relationships between 
psychological distress, QOL, immune function and overall survival.


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For example, Pereira showed that in human immunodeficiency virus-positive 
women, increased life stress correlated with progression and persistence of 
cervical neoplasia [46]. In a small study of patients with cervical dysplasia, 
patients with dysplasia and healthy controls had significant differences in cortisol 
levels [47]. Pereira et al. suggested that psychoneuroimmunological mechanisms 
play a role in human papillomavirus (HPV)-mediated cervical neoplasia, the 
initiation point for development of invasive cancer [46].
Psychoneuroimmunological changes in patients with early cervical cell 
transformation emphases effect on the regression and disappearance of HPV via a 
cell-mediated immune response involving T helper type 1 (TH1) cells, NK cells, 
and interleukin (IL)-10 [48, 49]. With inadequate immunity, HPV infection may 
become persistent. In addition, cigarette smoking may contribute to HPV 
infection via correlation of progression with increased serum cotinine 
concentrations [49].
2.6
Symptom distress assessment and interventions in cancer patients
Supportive care and symptom control are important aspects in the care of a 
woman with incurable cervical cancer. All too often, care is focused on treatment 
interventions to potentially lengthen life without equivalent intense focus on 
improving symptom control. 
One of the few stress interventions reported in a population of cervical cancer 
patients was in a randomized trial in cervical cancer survivors [50]. The survivors 
underwent psychosocial counseling sessions over the telephone, whereas the 
controls underwent “usual care.” The patients completed six counseling sessions 
of about 45-50 minutes in length in their preferred languages. The sessions 
consisted of five consecutive weekly sessions and a booster session delivered by a 
psychologist. QOL data and biological specimens were collected at baseline and 4 
months after enrollment. Significant improvements in QOL were noted in the 
intervention arm and these improvements were associated with significant 
immune system changes, most notably an increase in the TH1:TH2 cell ratio. The 
authors concluded that “the integration…interventions leading to enhanced QOL 
could result in improved clinical outcome including survival” [50]. Similar 
studies of other cancer types suggested that relaxation interventions can improve 
overall survival in patients with other types of cancers [51]. Importantly, 
Lutgendorf’s group showed that immune function can be preserved in cancer 
patients with integrative medicine/healing touch (stress reduction) intervention 
and resultant preservation of NK-cell cytotoxicity [30].
Few non pharmacologic QOL interventions have been performed in advanced 
cancer patients. Psychological interventions may help cancer patients in a variety 
of ways, including reducing the severity of side effects of cancer and its 
treatment, anxiety, and distress, and more recently, these interventions have been 
linked with improved immune function which may result in “improved OS 
durations” [30, 50, 51].  Interventions have included a variety of methods 
including telephone support and psychological counseling [52, 53]. Many of these 


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approaches are time consuming and not practical for patients nearing the end of 
life. 
Most studies evaluating the effectiveness of psychological/behavioral interventions 
are limited by poor methodology. A recent systematic review assessing randomized 
controlled trial designs using evaluated internal validity indicators suggested that 
the quality of such studies is suboptimal [54] That said, authors have reported 
psychoneuroimmunological effects of relaxation/guided imagery interventions
such as improved behavioral/coping metrics, including improved mood and 
decreased anxiety, nausea, vomiting, and anger  but also decreased levels of 
cortisol, IL-6, IL-10, and IL-12 and activity of NK cells and other immune 
modulators. Relaxation and guided imagery (R/GI) is a form of relaxing meditation 
in which involves systemic tensing and relaxing of various parts of the body 
progressing from feet to head. Through guided imagery, patients listen to recorded 
and/or spoken speech of specific positive thoughts associated with calmness, 
control and reduction of distress. 
Relaxation and Guided Imagery (R/GI) for reduction of distressing symptoms in 
cancer populations has been seen in multiple studies [55] [56, 57].  However, some 
have reported mixed results for the relief of anxiety and depression in people with 
cancer [58-60].  Importantly, impressive results have been reported in a group 
learning relaxation and imagery techniques for management of anxiety and 
discomfort during brachytherapy [61]. The patients received training and relaxation 
and guided imagery for 10 min and were given a cassette to use at home and in 
hospital.  In lung cancer patients undergoing radiation distressing symptom clusters 
include breathlessness, and anxiety and fatigue, thought to originate from a “stress” 
trigger [62]. During the 12 week study, the intervention involved a 40 min 
educational package plus coaching. An audiotape was also provided to patients and 
they were asked to listen daily. Significant effects on breathlessness, fatigue, 
anxiety and functional ability were found [57]. In a feasibility study of 86 patients, 
sessions lasted 90 minutes and held weekly for 6 weeks [55].  An improvement was 
seen in both impact of events scale and brief symptom inventory [55].
R/GI has also been used to address pain in cancer patients.  Kwekkeboom et al 
were able to show improvements in pain intensity, pain-related distress, and 
perceived control over pain using R/GI but little other data is available in this 
population [63]. Additional support for this method is detailed in Bonica's 
Management of Pain [64].
Immunomodulating effects as reported in the Nelson study [50] required extensive 
interventions such as time consuming phone call commitments and those described 
in Jon Cabot-Zinn’s mindfulness meditation curriculum, which includes an 8-week 
review of the benefits and techniques of mindful meditation as well as 
recommended daily homework [65, 66]. Nelson and colleagues conducted six 
counseling sessions 45-50 minutes in length (five consecutive weekly sessions and 
a booster session 1 month after completion of sessions. Most studies suggest that 


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active/experienced mind-body practice techniques (e.g., mindfulness meditation) 
can be more effective than less/novice practiced techniques [67, 68].
The literature contains insufficient data to support the exact “dose” in a relaxation 
stress-reduction intervention [65, 69, 70]. It does contain data supporting good 
results with experience and increased frequency and duration of practice, but the 
dose at which such results are obtained remains unknown. According to available 
data, results require practice most days of the week and sessions at least 20-30
minutes long [20, 67, 68, 71-73]. Most studies showing the effectiveness also 
demonstrate that reminder phone calls and instruction to practice these 
interventions daily at home are effective [50, 65, 72].
The present study is designed to evaluate the effect of E-adrenergic blockade and 
R/GI on advanced incurable cervical cancer. The reason for this Phase II feasibility 
study design is based on the following:
1. The best clinical practice in these patients is to offer a supportive care 
consultation if available for symptom control regardless of therapy offered
2. There is concern regarding the feasibility and acceptability for patients nearing 
the end of their life to accrue to a trial that doesn’t use a new agent as its targeted 
intervention, this design will allow assessment of feasibility/acceptability.
3. Beta blockades have not been used in a clinical population nearing the end of 
life and with advanced cancer and tolerability will need to be assessed. This 
trial will allow for an upward titration of B blockade with close observation of 
BP and Pulse.
4. R/GI will allow for additional QOL benefits for these patients at this important 
time point and will allow the evaluation of the combination on translational end 
points and then allow us to proceed with planned randomized phase II to tease 
out the individual influences.  
2.7
E-Adrenergic Receptors and Their Roles in Cancer Development
Four E-adrenergic receptors (bARs) exist, and they have been characterized 
according to their physiological functions. bARs are G protein-coupled receptors 
that are the targets of catecholamines such as norepinephrine and epinephrine and 
whose primary function is to transmit information from the extracellular 
environment to the interior of the cell, leading to activation of adenylyl cyclase 
and accumulation of the secondary messenger cAMP [20]. E1-adrenergic 
receptors have chronotropic effects (affecting the heart rate and thereby increasing 
cardiac output), release renin, and increase lipolysis. E2-adrenergic receptors 
cause dilation of blood vessels and bronchioles, stimulate insulin release, and 
increase lipolysis, glycogenolysis, and gluconeogenesis. E3-adrenergic receptors 


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are involved in lipolysis and mediate vascular relaxation but are activated by 
higher concentrations of catecholamines. Researchers have identified bARs in 
breast, pancreatic, ovarian, lung, head and neck, prostate, and colon cancer cases 
[34-38, 74-76]. Palm and associates found that 70-90% of human tissue 
microarray specimens of breast, colon, and prostate tumors expressed E2-
adrenergic receptor and demonstrated using an in vivo model that the incidence of 
lymph node metastases increased with the administration of norepinephrine but
decreased with the introduction of the E-blocker propranolol [37]. Until recently, 
whether the direct neuroendocrine regulation of tumor cell biology demonstrated 
convincingly in in vitro and in vivo ovarian cancer models is biologically relevant 
to primary human tumors as well as whether the regulation correlated with 
biobehavioral characteristics was unclear [34]. In 2009, Lutgendorf and 
colleagues explored this relationship by identifying human ovarian tumor 
specimens that had high (high depressive symptoms and low social support; n = 
10) versus those with low (low depressive symptoms and high social support; n = 
10) biobehavioral risk profiles [29]. They found that gene expression profiles in 
primary ovarian tumor specimens are systematically altered in association with 
the patient’s biobehavioral risk factors, and promoter-based informatics analyses 
confirmed that E-adrenergic transcription control pathways are the key mediators 
of differences in gene expression profiles. Additionally, tissue levels of the 
sympathetic catecholamine norepinephrine were elevated in ovarian tumor 
specimens obtained from patients with high biobehavioral risk profiles [77].
Studies of other cancers support the importance of bARs in cancer progression. 
Importantly for our proposed study, oral squamous cell carcinoma (potentially 
HPV-related) cells highly express E2-adrenergic receptor, and its expression is 
significantly correlated with lymph node metastasis and advanced tumor stages 
cancer patients [75]. Also, regarding the connection between smoking and 
cervical dysplasia, researchers have noted that nicotine promotes gastric, 
pancreatic, lung, esophageal, and colon tumor and melanoma growth and anti-
angiogenesis via E-adrenergic activation (E2-adrenoreceptors with subsequent 
stimulation of cyclooxygenase-2, prostaglandin E2, and VEGF) [76, 78-83].
2.8
E-Blockers
Propranolol is a first-generation E-blocker that non-selectively blocks both E1- and 
E2-adrenergic receptors. We selected this E-blocker for our proposal, because it is 
still commonly used and researchers have used it with an orthotopic mouse model 
of ovarian cancer [23, 75, 76, 81, 84]. Thaker and colleagues demonstrated that 
chronic behavioral stress resulted in increased levels of tissue catecholamines, an 
increased tumor burden, and increasingly invasive growth of ovarian carcinoma in 
that model. These effects appeared to be mediated by activation of the tumor cell 
cyclic AMP-protein kinase A signaling pathway by E2-adrenergic receptor. These 
stressed mouse tumors had higher expression of angiogenic factors, including 
VEGF, than did control mouse tumors [85]. The effects of chronic behavioral 


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stress on expression of angiogenic factors can be abrogated by E-blockers, thereby 
emphasizing the importance of that trial in demonstrating the feasibility of adding 
the use of E-blockers to standard palliative approaches to treatment in and care for 
cervical cancer patients.
Recently, Diaz et al. [86] presented retrospective data on a cohort of ovarian 
cancer patients in whom use of E-blockers reduced the risk of death by 56% 
below that in nonusers. The data regarding the effectiveness of E-blockers may be 
most compelling in breast cancer patients [87]. For example, Powe et al. recently 
retrospectively studied breast cancer patients and showed that E-blocker–based 
therapy reduced the number of distant metastases, the incidence of cancer 
recurrence, and mortality rates, and others have shown that inhibiting the E΍-
adrenergic signaling pathway can reduce breast cancer progression and mortality 
[87, 88]. Also, showed improved relapse-free survival durations in patients with 
triple-negative breast cancers using beta-blockers [89]. Furthermore, use of E-
blockade in melanoma patients has received much recognition. Specifically, 
researchers demonstrated that use of E-blockers was associated with a reduced 
risk of progression of thick malignant melanoma and that E-blocker intake was 
associated with increased survival durations in melanoma patients [90, 91].
Laboratory data suggests that the effects of E-blockers on cancer cells are 
accomplished via blockade of adrenergic stimulation of increased noradrenaline, 
adrenaline, cortisol, and VEGF levels via E2-adrenergic receptor activation of the 
tumor cell cyclic AMP-protein kinase A signaling pathway [26, 85].
2.9
Angiogenesis, VEGF, and Cervical Cancer
In patients with cervical neoplasia, VEGF expression and microvessel density 
progressively increased during the transition of normal cervical epithelium to 
squamous cell carcinoma [92]. Furthermore, polymorphisms of VEGF genes may 
correlate with survival of early stage  cervical cancer by modulating angiogenesis 
as measured according to microvessel density [93]. In the animal laboratory 
model, increased tumor vascularization and enhanced expression of VEGF and 
matrix metalloproteinase-2 and -9 in tumor cells in stressed animals could be 
abrogated by the use of a E-adrenergic antagonist such as propranolol [23].
Extrapolating from this data and recognizing that the HPV-18 E6 oncoprotein 
induces VEGF transcription in a p53-dependent manner, decreasing the 
expression of VEGF in tumor cells by reducing the stress response may be an 
interesting method of cervical cancer therapy [94]. This is substantiated by the 
fact that VEGF receptor 2 is more highly expressed in cervical cancer cells than in 
normal cervical tissue controls [92, 93, 95]. High vascularity as measured 
according to microvessel density is associated with a positive lymph node status 
[96], poor prognosis, and increased risk of recurrence [97]. Five-year survival 
rates for cervical tumors with high and low microvessel densities are 50% and 


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65%, respectively [98]. Finally, serum VEGF levels are significantly elevated in 
cervical cancer patients with large and/or high-grade tumors or who smoke [95].
2.10
Cervical Cancer Cell Lines, Cervical Cancer Tissue, and Adrenergic 
Receptors
In our lab we evaluated human cervical cancer samples obtained at the time of 
diagnosis from 168 women. ADRB1 and ADRB2 expression was examined using 
immunohistochemical peroxidase staining and semi-quantitative scores were 
related to patient outcome. In addition, we examined the effects of catecholamines 
on production of pro-angiogenic factors (VEGF, IL8) by cervical cancer cell lines 
(SiHa and Caski) using qRT-PCR.
The median age of patients was 45.3 (range 22 – 83). Among the 168 tumor 
samples evaluated, 85% had increased ADRB1 expression and 61% had increased 
ADRB2 expression. Tumor stage or grade were not related to ADRB expression. 
ADRB1 expression was not related to overall patient survival (p = 0.86); 
however, ADRB2 was significantly related (mean 146 months for those with 
increased expression vs. 206 months for those with low or absent expression; p = 
0.038). Upon stimulation with norepinephrine or isoproterenol, the levels of 
VEGF did not change appreciably, but the levels of IL8 increased by 3.5 – 6-fold 
(p<0.001). These data support the hypothesis that ADRB2 might play a pivotal 
role in cervical cancer growth and progression and have potential clinical 
implications for new therapeutic strategies.
2.11
Summary
Women diagnosed with recurrent cervical cancer are faced with a dearth of 
effective chemotherapy or other therapies in a recurrent setting; thereby, using a 
low side effect drug such as propranolol beneficial in a population with such a 
short time of overall survival is appropriate. There are many other downstream 
effectors of the beta-adrenergic receptor which are equally important in 
carcinogenesis that will need to be explored in the future.
Because E-blocker use has been prevalent in patients with cardiovascular disease 
for years, they are known to be safe and offer the relatively inexpensive 
opportunity to test our hypothesis regarding the effects of neurobiological 
stressors on cervical cancer in our proposed study. Our hypothesis is that the 
intervention of a beta-adrenergic blockade in conjunction with “minimal dose” 
relaxation intervention in advanced cervical cancer patients will result in stable to 
improved quality of life and improved overall survival. This improved QOL and 
OS will correlate with decreases in serum levels of interleukin 6 and 8 and VEGF.  
Furthermore, attention to QOL at the end of life has become of the utmost 
importance in caring for patients with advanced cancer. ASCO recently supported 
the emphasis on best supportive care in stating that “substantial evidence 
demonstrates that palliative care—when combined with standard cancer care or as 


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the main focus of care—leads to better patient and caregiver outcomes.” These 
include improvement in symptoms, QOL, and patient satisfaction, with reduced 
caregiver burden. Earlier involvement of palliative care also leads to more 
appropriate referral to and use of hospice, and reduced use of futile intensive care 
[19] The proposed study emphasizes avoidance of treatment of recurrent incurable 
cervical cancer with standard second line therapies, in which response durations 
have been dismal. Instead, this proposal integrates an R/GI therapy intervention 
and low-risk treatment with a E-blocker, which is supported by strong preclinical 
and retrospective data and expected to result in maintained OS decreased distress 
and improved quality of life.
3.0
PATIENT ELIGIBILITY
3.1
Inclusion:
3.1.1
Proven recurrent cervical cancer of any histology not eligible for curative 
radiotherapy or surgery.
3.1.2
Failed chemotherapy for first recurrence (excluding chemotherapy with 
concurrent irradiation) or refractory to first line systemic therapy.
3.1.3
Measurable or non-measurable disease
3.1.4
Unlimited prior therapies
3.2
Exclusion:
3.2.1
Patients whose disease may be cured by surgery or radiotherapy.
3.2.2
Contraindication to use of a E-blocker.(uncontrolled DM, COPD-unstable,
Bradycardia <50 BPM)
3.2.3
Already receiving a E-blocker.
3.2.4
Performance status > 3. Must have had treatment for first line recurrence
3.2.5
Prior radiation therapy for localized cancer of the breast, head and neck, or 
skin is permitted provided that it was completed more than 3 years prior to 
registration, and the patient remains free of recurrent or metastatic disease. 
3.2.6
With the exception of non-melanoma skin cancer and other specific 
malignancies as noted above, patients with other invasive malignancies who 
had (or have) any evidence of the other cancer present within the last five 
years or whose previous cancer treatment contraindicates this protocol 
therapy are excluded.


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3.2.7
Use of systemic glucocorticoids such as Prednisone or Decadron in the last 
month for greater than one week
3.2.8
Inability to accurately answer questions (e.g. dementia, brain metastases) or 
speak English or Spanish.
3.2.9
Cirrhosis of the liver
3.2.10 Patients under the age of 18
3.2.11 History of comorbid conditions: Addison’s disease, autoimmune hepatitis, 
hepatitis B, hepatitis C, AIDS or HIV, lupus erythematosus, mixed 
connective tissue disease, rheumatoid arthritis. 
3.2.12 Hypersensitivity to propranolol, or beta-blockers
3.2.13 Uncompensated congestive heart failure 
3.2.14 Cardiogenic shock
3.2.15 Severe sinus bradycardia; heart block, second or third degree or sick sinus 
syndrome (if no artificial pacemaker present)
3.2.16 Severe hyperactive airway disease (chronic obstructive pulmonary disease, 
asthma)
3.2.17 Any patients on Avastin or any other anti-angiogenic drugs.
3.2.18 Patients with brittle diabetes mellitus (DM) Brittle diabetes mellitus is a type 
of diabetes when a person's blood glucose (sugar) level often swings quickly 
from high to low and from low to high. Also called "unstable diabetes" or 
"labile diabetes."
3.2.19 Patients participating in or who plan to participate in other trials during the 
course of this study.
3.2.20 Patients actively using cocaine.
3.2.21 Cannot be receiving any other active neoplastic treatment during 4 months 
of study.
4.0
STUDY MODALITIES
4.1
Propranolol (InderalR)


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4.1.1
Indication and Use: 
Used for treatment of hypertension, cardio protection after a myocardial 
infarction, and management of cardiac arrhythmias such as atrial 
fibrillation.  Also it can be used in the treatment of migraines or essential 
tremor.
4.1.2
Formulation: 
Propranolol is supplied as tablets in the following strengths: 10 mg, 20 
mg, 40 mg, 60 mg, and 80 mg.
4.1.3
Storage:  
Store tablets at room temperature between 20-25oC (68-77oF) and away 
from light and moisture
4.1.4
Administration:  
A starting dose of propranolol 20 mg is taken by mouth twice a day (40 
mg/day). If the patient tolerates the initial dose (no hypotension or 
bradycardia) the dose will be increased to 40 mg by mouth twice a day at 
the start of the second month of therapy. For patients >65 years old the 
dose will stay at 20 mg by mouth twice a day. Dose reductions to 10 mg 
administered by mouth twice a day will be allowed for titration for 
optimization of BP and pulse. All dose adjustments will be made in the 
clinic.
4.1.5
Onset and Duration of Action:  
Propranolol is administered orally or intravenously. After oral 
administration of immediate-release propranolol, the dose is almost 
completely absorbed, and peak concentrations are achieved within 60-90
minutes. Co-administration with food appears to enhance bioavailability.
Despite complete absorption, propranolol has a variable bioavailability 
due to extensive first-pass metabolism.  Hepatic impairment will therefore 
increase its bioavailability.  The main metabolite 4-hydroxypropranolol, 
with a longer half-life (5.2-7.5 hours) than the parent compound (3-4
hours) is also pharmacologically active.  
4.1.6
Metabolism and Excretion: 
Propranolol is highly lipophilic and, as a result, is widely distributed 
throughout the body. It readily crosses the blood-brain barrier and the 
placenta, and is distributed into breast milk.  Propranolol is greater than 
90% bound to plasma proteins, primarily alpha-acidic glycoprotein which 
is elevated in conditions of physiological stress such as inflammation or 
cancer.
Propranolol is extensively metabolized upon first pass through 


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the liver by CYP2D6 isoenzymes, with secondary pathways via CYP2C19
and CYP1A2. The drug also binds to and saturates non-specific hepatic 
binding sites before the drug reaches the systemic circulation. An 
equipotent, pharmacologically active metabolite, 4-hydroxy-propranolol, 
is produced with the initiation of oral therapy, but it is eliminated faster 
than the parent drug because with chronic or IV therapy, this metabolite is 
produced to a lesser degree.
Excretion of propranolol occurs renally, primarily as metabolites, with 
only 1-4% of a dose excreted fecally as unchanged drug. The elimination 
half-life of propranolol ranges from 2-6 hours, with protein binding and 
chronic administration yielding longer half-lives, possibly due to 
saturation of liver binding sites and/or systemic clearance. In patients with 
severe renal dysfunction, fecal elimination may increase to compensate for 
decreased renal excretory processes. Propranolol is not appreciably 
removed by hemodialysis. Caution is recommended administering 
propranolol in patients with altered renal or hepatic function as
well as in elderly population because of altered 
pharmacokinetics, specifically extended half-life/decreased 
elimination.
4.1.7
Drug Interactions: (www.clinicalpharmacology-ip.com)
Adenosine
Anti-arrhythmic drugs (flecainide, propafenone, moricizine, encainide)
Amiodarone
Bretyllium
Calcium-blocking blood pressure drugs such as diltiazem,  
nifedipine, and verapamil
Certain high blood pressure medications such as reserpine
Cardiac glycosides
Epinephrine
Insulin
Levodopa
Lidocaine
Monoamine oxidase inhibitors
Oral diabetes drugs such as glyburide
Prazosin
Quinidine
Rifampin
Theophylline
4.1.8 Contraindications and Side Effects:  
The adverse effects of propranolol are generally mild and temporary.  These 
side effects usually occur at the onset of therapy and diminish over time. 
Propranolol is contraindicated in patients with sinus bradycardia, cardiogenic 


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shock, bronchial asthma, or allergic to propranolol. Use with care in patients 
with congestive heart failure.
Side Effects: Sinus bradycardia, hypotension, AV block, congestive heart 
failure in patients with preexisting left ventricular dysfunction, depression, 
confusion, hallucinations; or Mask signs of hypoglycemia, Agranulocytosis, 
decreased sex drive, impotence, or difficulty having an orgasm; nausea, 
vomiting, diarrhea, constipation, stomach cramps; sleep problems (insomnia); 
or tired feeling.
Please refer to Appendix O & P - Common Side Effects of Beta Blockers.
4.1.9 Supplier:  
Propranolol will be provided free of charge to the patients and distributed by 
the Mays Clinic Pharmacy, MD Anderson Cancer Center, and the LBJ
Pharmacy. Patients will receive monthly supplies.  
4.1.10 Pill Calendar Diary (Appendix M, N):
A pill calendar diary will be submitted at each visit along with the pill bottle 
for verification. Calendars, empty bottles and any unused medication will be 
collected at each appointment before the next refill is given to the patient.
4.1.11 Relaxation Practice Log (Appendix Q, R)
The relaxation practice log is to help keep track of relaxation practice. A 
relaxation practice log will be submitted at each clinic visit.
5.0
PROPOSED TREATMENT/STUDY PLAN
5.1
Dosing of Propranolol
A pill diary will be provided that is a monthly calendar on which patients will 
record the study medication they take each day.  Every dose will be documented 
and if doses are missed, the patient will be asked to note why they missed a dose.  
Calendars, empty bottles and any unused medication will be collected at each 
appointment before the next refill is given to the patient.
Propranolol will be provided to the participant free of charge.
A starting dose of propranolol 20 mg is taken by mouth twice a day (40 mg/day).
If the patient tolerates the initial dose (no hypotension or bradycardia) the dose 
will be increased to 40 mg by mouth twice a day at the start of the second month 
of therapy. This will ideally be titrated up to 40 mg twice a day in order to 
maintain a heart rate between 50 to 80 bpm without symptoms or hypotension 
(systolic BP <110 or diastolic BP <50). For patients > 65 years old the dose will 
stay at 20 mg by mouth twice a day. Dose reduction to 10 mg administered by 


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mouth twice a day will be allowed for titration for optimization of BP and pulse. 
All dose adjustments will be made in the clinic.
To insure compliance, patients will fill out pill calendar diaries that will be 
collected on a monthly basis.
If removed from study, all patients will be weaned off the medication over the 
following 2 weeks. The dose will be reduced by 50% for 7 days then will be 
reduced to 25% of the dose for 7 days then discontinue completely. For patients 
that experience adverse effects during weaning the period of time can be 
increased as deemed appropriate. 
5.2
Relaxation Intervention
Three 20-minute audio relaxation/guided imagery (R/GI) exercises (MP3) will be 
provided to each patient (in English or Spanish). Patients will be instructed to listen 
to the MP3 two times a week and make recordings in a standard diary regarding 
whether they were able to complete the session and whether they had any 
difficulties in doing so (difficulties recorded in the diary should include lack of 
time, unexpected interruption, noise, the presence of children, and other 
distractions) [99]. To ensure compliance, patients will complete relaxation exercise 
activity logs as well as pill calendar diaries. These will be collected monthly. (Pill 
diary)
5.3
Methodology
After a patient is deemed eligible for the study, she will be asked to provide consent 
to participate. If consent is given, at this time the patient will be given a 
demographic questionnaire (age, race, marital status, and smoking history) and the 
Functional Assessment of Chronic Illness Therapy-Cervix (FACT-Cx), Brief Pain 
Inventory (BPI),
MD Anderson Symptom Inventory (MDASI) and Hospital 
Anxiety and Depression Scale (HADS). Additionally, blood will be drawn from the 
patient in the clinic prior to the start of the intervention for measurement of baseline 
IL-6, IL-8, IL-10, circulating HPV DNA, and VEGF levels.
Upon enrollment, all patients will be instructed to listen to MP3-
relaxation/guided imagery audio intervention. Patients on protocol will be referred 
for supportive/palliative care consultation at MDACC or LBJ. At the end of four 
months, patients will have the option of continuing treatment until intolerability of 
the treatment, disease progression or death. Propranolol will be provided to the 
participants free of charge. Propranolol will be administered at 20 mg twice a
day (40 mg/day). This dose will ideally be titrated up to 40 mg twice a day to 
maintain a heart rate of 50-80 beats per minute without causing hypotension 
(systolic blood pressure [BP] < 110 mmHg or diastolic BP < 50 mmHg). For 
patients more than 65 years old, the starting dose will be 20 mg given by mouth
twice a day. Dose reduction to 10 mg administered by mouth twice a day will be 
allowed for titration for optimization of BP and pulse. All dose adjustments will 


2013-0113
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be made in the clinic. Blood draws and completed surveys of biobehavioral 
measures (FACT-Cx, MDASI, HADS, BPI and smoking history) will be collected at 
baseline and again after the completion of every two cycles (1 month = one cycle) until
the 4-month time point. The HADS will be scored and evaluated within 24 hours of 
completion. The Hospital Anxiety and Depression Scale (HADS) is a 14 item 
self-administered scale to detect states of depression and anxiety. Respondents 
answer questions using a scale of 0 (not at all) to 3 (very often).  A HADS score 
of 15 or higher defines clinical depression or anxiety, and those patients will be 
assessed by their physician, and, if appropriate, referred to psychiatry. Scoring 
will be done by the research personnel.
Feasibility is determined by completion of three time points (TP0, 2, 4 mos).
Patients who wish to continue on the regimen may do so until voluntary 
discontinuation, intolerability, disease progression, or death. The patient will be 
followed until death with assessment of medical notes in clinic station. Reason for 
study termination will be recorded.
CT of chest, abdomen, and pelvis will be obtained at baseline within 6 weeks prior 
to starting treatment and then per MD discretion or worsening of symptoms.
5.4
Quality of Life Analysis
5.4.1
Functional Assessment of Chronic Illness Therapy-Cervix (FACT-Cx) and 
MDASI.  
QOL will be assessed using the Functional Assessment of Cancer Therapy-
Cervix (FACT-Cx).  The FACT-CX is comprised of 27-item general cancer 
concerns (FACT-G) and an additional 10-item cervical cancer specific 
scale. This summary score captures the FACT-G QOL dimensions of 
Physical, Functional, Social and Emotional Well-Being, plus the Cervical 
Cancer Subscale (7 items).  Scoring will be done by the research personnel. 
The Trial Outcome Index is the sum of the Physical Well-Being (PWB), 
Functional Well-Being (FWB), and "additional concerns" subscales. The 
TOI is an efficient summary index of physical/functional outcomes. It is a 
common endpoint used in clinical trials, because it is responsive to change 
in physical/functional outcomes, sometimes more than a total (overall) 
multidimensional aggregated score which includes social and emotional 
well-being. While social and emotional well-being are very important to 
quality of life, they are not as likely to change as quickly or dramatically 
over-time or in response to therapy.  The timing of the QOL and depression 
assessments will be administered after every two months [100, 101].
Symptom distress symptoms will be assessed by the MDASI, which 
assesses 13 common cancer-related symptoms, including pain, and six 
symptom-interference items, each rated over a 24-h recall period on a 0–
10 scale. A composite interference score will be calculated as the mean of 
all six MDASI interference items for each patient [102, 103].


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5.4.2
Demographics. 
The patients’ demographic characteristics will be collected before R/GI 
therapy and E-blockade. These include age, ethnicity, socioeconomic status, 
do-not-resuscitate status before and after enrollment, prior treatments, 
successive treatments, smoking status, baseline physical well-being 
(according to the TOI), and ECOG performance status.
5.4.3
The Brief Pain Inventory (BPI)
The BPI is a 9-item self-report instrument designed to assess pain in 
cancer and other diseases. The BPI has demonstrated reliability and 
validity across cultures and languages and has been used to study the 
effectiveness of pain treatment [104].
5.4.4
Experimental design:  Translational Components
In this proposed study, we will have the benefit of obtaining blood 
specimens prior to and after administration of propranolol and will be able 
to generate preliminary data on the effects of propranolol on IL-6, IL-8, Il-
10, CRP, Circulating HPV DNA and VEGF levels These data then can be 
correlated with biobehavioral measures that we will collect.
5.4.4.1 IL-6:
IL-6 expression is regulated by neural and endocrine responses to 
stress via feedback loops and by the hypothalamic-pituitary-adrenal 
axis at the pituitary and adrenal gland level [105, 106] IL-6 levels 
are elevated along with sympathetic activation (including cortisone 
and norepinephrine levels by acute and chronic stress and 
depression whereas IL-6 levels decrease following treatment of 
depression [83],[105]
[107],[108],[109],[110],[111].
IL-6 is 
secreted by many cell types, including ovarian tumor cells, and is 
involved in many pathological processes in cancer patients. IL-6
stimulates proliferation of tumor cells [112, 113], enhances tumor-
cell migration and attachment [113], promotes invasion of vascular 
endothelial cells by tumors [114] and angiogenesis [115], and is 
associated with tumor progression, shortened disease-free intervals, 
and poor OS [77, 116]. Oral cancer cells stressed by high levels of 
cortisol exhibit increased IL-6 expression and increased 
proliferation [111]. In melanoma cell lines, the presence of 
norepinephrine results in increased expression of VEGF, IL-8, and 
IL-6 [83]. In a study of patients with cervical dysplasia, IL-6 and IL-
8 concentrations in cervicovaginal washings were higher in cervical 
carcinoma in situ (non-invasive dysplasia) patients than in normal 
controls and higher still in cervical cancer patients than in carcinoma 


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in situ patients [117]. Although relatively little data on IL-6 and 
cervical cancer are available, interestingly, stress hormones 
(norepinephrine and cortisol) can increase IL-6 mRNA production 
in oral squamous cell carcinoma cells, and this effect is blocked by 
treatment with propranolol. Researchers also have documented 
expression of E1- and E2-adrenergic receptors using polymerase 
chain reaction [111].
5.4.4.1.1
Methods: 
IL-6 levels in plasma will be measured using enzyme-
linked immunosorbent assays (ELISAs; R&D Systems, 
Minneapolis, MN), with results interpolated from using 
the standard curve provided with the ELISA kit. IL-6–
expressing specimens with sensitivity below that of below 
the sensitivity cutoff for the regular assay will be 
quantitated 
using 
high-sensitivity 
ELISA 
(R&D 
Systems). 
5.4.4.2 IL-10:
IL-10 is a counterregulatory or immunosuppressive mediator of 
stress-induced immunosuppression. IL-10 is extremely important to 
the initial transformation of cervical dysplasia to premalignant 
lesions. Investigators have shown that IL-10 expression is directly 
proportional to the development of HPV-induced cervical cancer 
[48]. Furthermore, in mouse models, stress-induced increases in IL-
10 expression can be prevented by treatment with nadolol as well as 
a benzodiazepine [118]. Furthermore in a study of behavioral 
(telephone mediated) interventions, improvement in QOL seen in 
the intervention cohort was correlated with an inverse association 
between modulation of QOL and serum levels of IL-10 as indicated 
by the mean and standard error of the mean for a cohort of individual 
measurements [50].
5.4.4.2.1 Methods:
Serum levels of IL-10 (lower limit of detection, 0.5 
pg/mL) will be measured in triplicate using standard 
ELISA (R&D Systems).
5.4.4.3 IL-8:
Chronic stress is associated with increase IL-8 levels [119]. IL-8 has 
a key role in regulation of angiogenesis, chemotaxis, and 


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enhancement of growth in a variety of tumors [120-122]. It is 
produced by tumor cells and macrophages [123]. In melanoma and 
ovarian cancer cell lines, treatment with norepinephrine has resulted 
in increased expression of VEGF, IL-8, and IL-6 [83, 119]. IL-8
contributes to the migration of tumor cells toward blood vessels and 
provides proliferative and antiapoptotic signals to tumor cells [124].
IL-8 overexpression is associated with advanced disease stage, high 
tumor grade, and decreased OS durations in cervical cancer patients 
[122]. IL-8 is thought to have an effect on tumor growth owing to 
expression of an angiogenic factor supplied by macrophages within 
and around cervical tumors. IL-8 expression has correlated with 
microvessel counts in cervical cancer patients [122], and 
microvessel density correlates with radioresistance and decreased 
OS duration [125]. Poorly oxygenated cervical tumors have 
increased microvessel densities, and this has correlated with 
decreased survival duration. Therefore, we hypothesize that IL-8 is 
a surrogate for angiogenesis changes that should be inhibited by the 
administration of propranolol.
5.4.4.3.1 Methods:
IL-8 expression in plasma will be measured using ELISA (R&D 
Systems), with the results interpolated from using the standard curve 
provided with the ELISA kit.
5.4.4.4 VEGF: 
VEGF is one of the most potent proangiogenic molecules, inducing 
endothelial cells in vascular microvessels near tumors to proliferate 
and migrate and inducing alteration of their patterns of gene 
expression in favor of angiogenesis [126]. VEGF makes cells hyper-
permeable, resulting in conditions favorable for angiogenesis in the 
extracellular matrix [127]. VEGF is produced by tumor cells, 
macrophages, and other cells. VEGF expression has been linked 
with norepinephrine stimulation of proliferation of cancer cell lines 
[83]. VEGF is critical to the growth and progression of cervical 
cancers and is a poor prognostic marker as consistent increases in 
VEGF expression are seen with increasing disease severity, and 
increased serum VEGF expression levels in other tumors are 
associated with metastatic disease and poor survival [98, 128, 129].
5.4.4.4.1 Methods:
Plasma VEGF expression will be measured using a 
standard ELISA kit (R&D Systems) (88). The minimum 
detectable serum level of VEGF = 5 pg/mL. 


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5.4.4.5 Circulating HPV
ctDNA can be detected in plasma of cervical cancer patients over 
stage I and HPV ctDNA concentration has been found to reflect 
tumor burden. In addition to its potential prognostic and predictive 
value, HPV mutation insertion is likely to constitute a new 
molecular surrogate of minimal residual disease and of subclinical 
relapse in HPV-associated tumor. This study will initially look at 
feasibility of obtaining this data in these patients with advanced 
recurrent cervical cancer [132, 133].
5.4.4.5.1
Methods
Plasma obtained from cervical cancer patients will be 
analyzed for HPV components in circulating cell-free 
DNA. DNA extraction will be performed using the 
Qiagen DNA extraction mini kit (Qiagen Biosciences, 
Germantown, MD). Quantification of target HPV genes 
(E2, E6, E7, L1 and L2) will be analyzed by Real-Time 
PCR using the Taqman Assay (Applied Biosystems, 
Foster City, CA). b-globin, GAPDH or b-actin will be 
used as a loading control. DNA concentration will be 
expressed as genome equivalents/per milliliter (GE/mL), 
as previously shown by our group (Kamat et al., 2006). 
5.4.4.6 Indirect calorimeter (on patients accrued at MDACC)
Cachexia is not only associated with poor outcomes, but also with
an unfavorable response to drug treatment and poor quality of life. 
It has been observed in patients with cancer that survival is impaired 
already at a weight loss of 5%; Weight loss exceeding 30% is 
incompatible with life. It is among the most common 
misconceptions that one of the underlying causes of cachexia is 
anorexia, i.e. loss of appetite. Although anorexia is certainly a 
common feature of the diseases leading to the development of 
cachexia, this feature alone cannot explain the metabolic changes 
observed during this perturbation. Importantly, nutritional 
supplementation cannot reverse the process of losing weight in 
patients with genuine cachexia, which is possible in patients who 
suffer from starvation or anorexia. Still, nutritional aspects have to 
be considered when treating patients with cachexia. Weight loss in 
the cachectic patient predominantly affects muscle protein, 


2013-0113
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Page 27
however, bone and fat tissue are likewise affected later in the course 
of the disease [134]. The factors that trigger the progression from 
clinically and body weight stable, ambulatory CHF to cardiac 
cachexia remain poorly understood. The timelines differ widely 
between patients. We will aim to see effect of Beta Blockade on 
resting energy use.
Using the Indirect Calorimeter (manufactured by Microlife) each 
patient had their oxygen consumption (Vo2) and carbon dioxide 
production (Vco2) measured until recordings were in a steady state 
for 15–20 min. The total energy expenditure was calculated to 
determine the measured resting energy expenditure (MREE) under 
conditions of rest. The oxygen and carbon dioxide sensors were 
calibrated for accuracy before each measurement. Use of the indirect 
calorimeter takes roughly 15 minutes. Resting Energy Expenditure: 
Formulae for measuring resting energy expenditure (REE), such as 
the Harris-Benedict equation, may underestimate an individual’s 
caloric requirements [135, 136]. A more accurate measurement of 
the REE can be made using indirect calorimeter. Each individual’s 
REE measurement will take approximately 10-15 minutes using a 
handheld indirect calorimeter (MedGem 101, (MG); HealthTech, 
Golden, CO), at baseline (+/- 3 days) and at day 58 (+/-
3days).
Measurements with the MG indirect calorimeter used 
single-use disposable mouthpieces and a noseclip for collection of 
expired air. Using the MG indirect calorimeter each patient has their 
oxygen consumption (Vo2 (ml/min)) measured and REE (kcal/day). 
[2] 
6.0
SAFETY PLAN AND CRITERIA FOR REMOVAL FROM STUDY
6. 1 Patient Safety
A number of measures will be taken to ensure the safety of patients participating in 
this trial. These measures will be addressed through exclusion criteria (see Section 
3.2) and routine monitoring as follows:
Patients enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this study. 
Safety evaluations will consist of medical interviews, recording of adverse events, 
physical examinations, blood pressure, and laboratory measurements (see Section 
8.1). Patients will be evaluated for adverse events (all grades), serious adverse 
events, and adverse events requiring study drug interruption or discontinuation at 
each study visit for the duration of their participation in the study. Patients 
discontinued from the treatment phase of the study for any reason will be evaluated 
approximately 30 days (28-42 days) after the decision to discontinue treatment.


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6.2 Criteria for Removal from Study
6.2. 1
Patients will be removed from the study if they are unable to tolerate the 
lowest doses of the regimen because of toxicity.
6.2.2
Patients may withdraw from the study at any time for any reason. 
       
7.0
TREATMENT MODIFICATIONS
Propranolol can be dose reduced if the patient’s heart rate is less than 60 or systolic BP is 
less than 110 or diastolic less than 50 and showing symptoms at two different timepoints 
24 hours apart. Also if the patient has side effects from the beta-blocker a dose reduction 
can be performed as outlined in Table E. All dose reductions will be made in the clinic. 
The maximum dose for propranolol should be 40mg po twice a day. For patients > 65
years old the maximum dose will be 20 mg by mouth twice a day. All dose adjustments 
will be made in the clinic.
Table E
Modifications for Propranolol dosing
Regimen -1 Level
Regimen -2 Level
Starting Dose 20 
mg twice daily 
10 mg po bid (50%)
Discontinue
Maximum Dose 40 
mg twice daily 
30 mg po bid (25%)
20 mg po bid (50%)
7.1 Hypotension.  
Patients receiving propranolol should be monitored before each dose with 
measurement of blood pressure (see Section 5.0 Treatment Plan).  If the SBP is less 
than 110 or the DBP is less than 50 and showing symptoms at two different 
timepoints 24 hours apart, the patient should be dose modified to regimen level -1
(see Table E).  If after this dose modification there is still hypotension, then dose 
modify to regimen level -2 (see Table E).  If patient still encounters hypotension, 
then discontinue the propranolol.
7.2 Bradycardia.
Patients receiving propranolol should be monitored with a measurement of heart 
rate. If the heart rate is less than 50 or 50-60 and showing symptoms at two different 
timepoints 24 hours apart, the patient should be dose modified to regimen level -
1(see Table E). If after this dose modification there is still bradycardia, then dose 
modify to regimen level -2 (see Table E). If patient still encounters bradycardia, 
discontinue propranolol.
8.0
STUDY PARAMETERS AND SERIAL OBSERVATIONS


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8.1
Observations and Tests
The following observations and tests are to be performed and recorded. 
Observations
and Tests
Prior to 
Initial 
Study 
Treatment
On Treatment
Month 1
(+/- 7
days)
Month 2
(+/- 7
days)
Month 4
(+/- 7
days) 
End of 
Study (+/-
7 days)
History & Physical
1
4
Blood Pressure
1
8
8
8
8
Heart Rate
1
8
8
8
8
Toxicity Assessment
1
8
4
4
4
CBC/Differential/Platelets
1
4
4
4
Serum Creatinine
1
4
4
4
Bilirubin, SGOT, SGPT, 
Alkaline Phosphatase
1
4
4
4
Magnesium
1
4
4
4
C-Reactive Protein (CRP)
1
4
4
4
PT/INR, PTT
1
5
5
Serum Pregnancy test if 
childbearing potential 
exists
1
EKG
1
6
6
Indirect Calorimetry 
(MDA Pts. Only)
1
4
4
Palliative Supportive Care
1
6
6
QOL Surveys
3
7
7
Demographic information
3
Blood draw (TR)
3
7
7
MRI, PET or PET/CT 
Scan of Chest/Abd/Pelvis
2
6
Pill Diary
8
4
4
4
Relaxation Log
8
4
4
4
1. Must be obtained within 14 days prior to initiating propranolol therapy.
2. Must obtain CT, MRI or PET within 6 weeks prior to receiving any propranolol therapy. 
3. QOL Surveys (MDASI, HADS, BPI, and FACT-Cx), demographic information and 
translational blood to be performed prior to initial study treatment
4. Must be obtained within +/- 7 days prior to clinic visit.
5. For patients on prophylactic or therapeutic anticoagulation with warfarin, PT/INR should be 
monitored before. 
6. Only if clinically warranted.
7. Biobehavioral measures and QOL Surveys (MDASI, HADS, BPI, and FACT-Cx) are to be 
administered after completion of months 2 & 4 on trial and blood is to be drawn at clinic visit 
for translational purposes.


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8. Blood Pressure and Heart Rate will be checked prior to starting propranolol in the clinic by 
research nurse/clinic nurse. At 48-72 hours after starting treatment, blood pressure monitoring 
needs to be done in the clinic by research nurse/clinic nurse but if patient unable to return to 
clinic, research personnel will contact patient for blood pressure readings. After that 
time, patient should continue to monitor blood pressure daily with their personal 
blood pressure machine, at their local pharmacy, or in the clinic. If personally 
monitoring their blood pressure, the patient should contact the research nurse if the 
SBP is less than 110, the DBP is less than 50 or heart rate 50-60 and showing symptoms at 
two different timepoints 24 hours apart.
9.0
EVALUATION CRITERIA
The present study is designed to evaluate the effect of E-adrenergic blockade and R/GI on 
advanced incurable cervical cancer.
We define this trial to be feasible if FACT Cx, BPI, HADS, and MDASI scores can be 
calculated for (1) all evaluable subjects at baseline, (2) 87% of subjects (13 out of 15) at 
Month 2, and (3) 73% of subjects (11 out of 15) at Month 4. Patients are considered 
nonevaluable if they leave the study through disease specific death or progressive disease 
prior to Month 4, and they will be replaced. Disease specific death does not include death 
due to excessive toxicity. All other patients are considered evaluable. 
10.0
DURATION OF STUDY
Feasibility is determined by completion of three time points (TP0, 2, 4 mos). Patients who 
wish to continue on the regimen may do so until voluntary discontinuation, intolerability,
disease progression, or death. The patient will be followed until death with assessment of 
medical notes in clinic station.
We will terminate the study early if too many patients experience dose-limiting toxicities 
(DLTs). 
If removed from study, all patients will be weaned off the medication over the following 
2 weeks. The dose will be reduced by 50% for 7 days then will be reduced to 25% of the 
dose for 7 days then discontinue completely. For patients that experience adverse effects 
during weaning the period of time can be increased as deemed appropriate.
11.0
STUDY MONITORING AND REPORTING PROCEDURES
A consent form must be signed by the patient prior to entry into study. Current Federal 
Drug Administration (FDA), National Cancer Institute (NCI) and institutional regulations 
concerning informed consent will be followed. 
11.1
Reporting an Adverse Event.


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11.1.1 An Adverse Event (AE) is any unfavorable and unintended sign (including 
abnormal lab finding), symptom, or disease that occurs in a patient 
administered a medical treatment, whether the event is considered related 
or unrelated to the medical treatment.
11.1.2 In the event of a serious adverse event (SAE) the first concern will be for 
the safety of the subject.  Investigators are required to report to the 
Principal Investigator, who in turn must notify the IRB of any serious 
adverse events (SAE’S) that are possibly related to the study therapy, as 
per MDACC IRB guidelines.
11.1.3 An SAE is any sign, symptom or medical condition that emerges with 
propranolol treatment or during a post-treatment follow-up period that:
(1)
was not present at the start of treatment and is not a chronic 
condition that is part of the patient’s medical history, OR 
(2)
was present at the start of treatment or as part of the patient’s
medical history but worsened in severity and/or frequency during 
therapy.
AND that meets any of the following regulatory serious criteria:
x Results in death 
x Is life-threatening 
x Requires or prolongs inpatient hospitalization 
x Is disabling 
x Is a congenital anomaly/birth defect
x Is medically significant or requires medical or surgical intervention 
to prevent one of the outcomes listed above.
11.1.4
This study will utilize the Common Toxicity Criteria version 4.0 (CTC 
4.0) for defining and grading specific adverse events. 
Specific situations that require reporting to the IRB are summarized in 
the table below.
Unrelated
Unlikely
Possible
Probable
Definite
Grade 1
Unexpected & 
Expected
Not Required
Not Required
Grade 2
Unexpected
Not Required
7 Calendar days
Expected
Not Required
Not Required
Grade 3
Unexpected with 
hospitalization
7 Calendar days
7 Calendar days


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Unexpected 
without 
hospitalization
Not Required
7 Calendar days
Grade 3
Expected with 
hospitalization
7 Calendar days 
7 Calendar days
Expected without 
hospitalization
Not Required 
Not Required
Grade 4 & 5
Unexpected
24 hours
24 hours
3 Calendar days
Grade 4 & 5
Expected
24 hours 
24 hours
7 Calendar days
1) “24 hours; 3 calendar days” - the investigator must initially report the 
AE within 24 hours of learning of the event followed by a complete 
report within 3 calendar days of the initial 24 hour report.
2) “7 calendar days” - a complete report on the AE must be submitted to 
the IRB within 7 calendar days of the investigator learning of the 
event.
11.1.5 Any medical event equivalent to a CTCAE grade 3, 4 or 5 that precipitates 
hospitalization must be reported regardless of attribution and designation 
as expected or unexpected with exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions. This 
includes any grade 4 laboratory abnormalities that result in hospitalization.
11.1.6 Any event that results in persistent or significant disabilities/incapacities,
congenital anomalies, or birth defects must be reported if the event occurs.
11.2
Assessing Causality:
Investigators are required to assess whether there is a reasonable possibility that 
propranolol, caused or contributed to an adverse event.  The following general 
guidance may be used
11.2.1 Yes: if the temporal relationship of the clinical event to propranolol, 
administration makes a causal relationship possible, and other drugs, 
therapeutic interventions or underlying conditions do not provide a 
sufficient explanation for the observed event.
11.2.2 No: if the temporal relationship of the clinical event to propranolol, 
administration makes a causal relationship unlikely, or other drugs, 
therapeutic interventions or underlying conditions provide a sufficient 
explanation for the observed event.
11.3
Severe Adverse Event reporting: 


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11.3.1 The following events will require a serious adverse event report to be 
completed and reported to the Principal Investigator and the MD Anderson 
Cancer Center Institutional Review Board.
x
Unanticipated side effect (not mentioned in consent, protocol or 
drug brochure)
x
Event exceeds the nature, severity or frequency described in 
consent, protocol or drug brochure.
x
Event involves a discrepancy between what was actually done to 
the research subject and what the subject was informed of when 
signing consent.
x
Event requires discontinuation of study drug use.
x
Event necessitates admission to hospital unless the hospitalization 
is anticipated due to the subject’s disease or treatment.
x
Event prolongs a stay in a health care facility.
x
Event necessitates supportive treatment to prevent permanent 
impairment or damage.
x
Event negatively affects prognosis.
x
Event results in a new cancer.
x
Event results in significant, persistent or permanent harm or 
disability*.
x
Event results in death.
x
Any death within 30 days of receiving study drug.
x
A congenital anomaly/birth defect.  
x
Event necessitates supportive treatment to prevent permanent 
impairment or damage.
* Definition of disability: A substantial disruption of a person’s ability to 
conduct normal life functions.
11.3.2 Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
x
Life-threatening adverse drug experience: Any adverse drug 
experience, including grade 4 laboratory abnormalities, that places 
the patient or subject, in the view of the investigator, at immediate 
risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, 
might have caused death.
x
Unexpected adverse drug experience: Any adverse drug 
experience, the specificity or severity of which is not consistent 


2013-0113
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Page 34
with the current Investigator Brochure; or if an Investigator 
Brochure is not required or available, the specificity or severity of 
which is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, 
as amended.
x
“Unexpected”, as used in this definition, refers to an adverse drug 
experience that has not been previously observed (i.e., is not 
included in the Investigator Brochure) rather than an experience 
that is not anticipated based on the pharmacological properties of 
the pharmaceutical product.
12.0
STATISTICAL CONSIDERATIONS: 
This is a feasibility study. Feasibility is defined in terms of patient enrollment, 
completion of survey scales, and safety of beta-blocker regiment. Specifically, we will 
consider this trial feasible if:
1. on average, we enroll at least 1-2 patients each month.
2.
FACT-Cx, BPI, HADS, and MDASI scores can be calculated for (1) all evaluable 
subjects at baseline, (2) 87% of subjects (13 out of 15) at Month 2, and (3) 73% 
of subjects (11 out of 15) at Month 4; and
3.
Pr(St d~data) > 90% where St is the proportion of any grade 3-4 toxicities that 
are probably, possibly, or definitely related to the intervention.
Scores for the FACT-Cx can be calculated when at least 50% of the items on each 
subscale have been answered. A total score for the FACT-Cx can be calculated when at 
least 80% of the total items have been answered and each subscale has a score.
Scores for BPI: Pain Severity can only be calculated when all 4 items have been 
answered. Scores for BPI: Pain Interference can be calculated when at least 4 out of the 7 
items have been completed.
Scores for HADS: Anxiety can be calculated when at least 6 of the 7 anxiety items have 
been completed. Likewise, scores for HADS: Depression can be calculated when at least 
6 of the 7 depression items have been answered.
Scores for MDASI: Symptom Severity can be calculated when at least 7 of the 13 items 
have been completed. Scores for MDASI: Symptom Interference can be calculated when 
at least 4 of the 6 items have been completed.
Patients are considered nonevaluable if they leave the study through disease-specific death 
or progressive disease prior to Month 4, and they will not be replaced.  Disease-specific 
death does not include death due to excessive toxicity.  All other patients are considered 
evaluable.  In addition to calculating the percent of women who complete these quality of 


2013-0113
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Page 35
life (QoL) measures, we will calculate the percent of women completing combined 
intervention of twice daily beta blocker and twice weekly progressive muscle relaxation 
and guided imagery at Month 2 and Month 4.
The secondary objectives of this study are to estimate the impact of beta blocker and 
relaxation intervention on symptoms, anxiety, depression, pain and QoL.  We will examine
symptoms and symptom distress using the MDASI, anxiety and depression using HADS, 
pain using the BPI and QoL using the Trial Outcome Index (TOI) of the FACT-Cx.    
The exploratory objectives of this study are to measure changes in serum levels of IL-6, 
IL-8, IL-10, VEGF, CRP, and resting energy use via calorimeter, as well as to measure 
HPV components (e.g. E6 and E7) in circulating cell-free DNA. 
All secondary and exploratory endpoints will be examined graphically and through 
summary statistics. Ninety percent confidence intervals will be calculated for all endpoints, 
including feasibility endpoints.
We will recruit 20 patients to obtain 15 evaluable patients.  With 15 subjects, if we have 
data for 87% of the women at Month 2 and 73% of the women at Month 4, our exact 90% 
confidence intervals at Months 2 and Months 4 will extend from 64% to 98% at Month 2 
and 49% - 90% at Month 4.  Additionally, with 15 subjects, the boundaries of our 90% 
confidence interval for sample means will extend 0.43 standard deviations on either side 
of the sample mean. We will also track number of patients approached and, if appropriate, 
reasons for declining to participate.
13.0
DATA MANAGEMENT
13.1
Registration
13.1.1 When a patient is found to be eligible for study, a signed informed consent 
will be required by the managing physician.  
13.1.2 Questions concerning eligibility may be addressed to the Study Chair(s), 
Contact Person/Data Manager or Nurse Contact. A protocol number will 
be assigned.
13.1.3 All patient entries will be registered in CORe.  The following forms will 
be completed in a timely fashion and will be placed in the subject’s study 
chart.  (Appendices D-G and I-T).
14.0
TRANSLATIONAL RESEARCH (See Appendices H and I)
14. 1
Specimen Collection
Blood Draws:


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An approximately 28 mL (5-6 tsp) blood sample (2 green tops, 1 CPT tube) will 
be obtained at time of enrollment prior to the initiation of propranolol. All blood 
will be immediately processed and frozen in at least 5 aliquots at –80o C. The 
plasma will be used to perform ELISA assays for VEGF, IL-6, IL-8., and 
circulating HPV.
14.2
Specimen handling:
Plasma for detecting of cytokines and angiogenic markers: 20 ml (4-5 tsp) of whole 
venous blood is collected in two greentop tubes. The tubes of whole blood should 
be allowed to sit for 10 minutes or until clotting is complete. Centrifuge the tube 
at 3000 rpm for 10 minutes. Transfer the plasma using a transfer pipet. Store the 
plasma in polypropylene cryostorage tubes. Aliquot .2 ml per tube. Freeze within 
2 hrs of phlebotomy. 
14. 3
Types of Laboratory assays:
Multiplex ELISA for detecting IL-6, IL-8, VEGF. Multiplex ELISA will be carried 
out based on the manufacturer’s instruction for detecting both human and mouse 
IL-6, IL-8, VEGF,  in plasma collected at the visit prior to starting therapy, at the 
2nd mos of treatment and the 4th month of treatment Coupled with the Luminex 
xMAP®platform in a magnetic bead format, the MILLIPLEX® MAG Human 
Cytokine / Chemokine panel (Millipore Corporation, Billerica, MA)  allows us to 
quantitative multiplex detection of dozens of analytes simultaneously, which can 
dramatically improve productivity. 
Microarray will be performed at Genomics Core Facility.  RNA will be isolated 
from PBMCs using MirVana RNA extraction. RNA extracted from patients 
before and after treatment will be sent to Core Facility for microarray analysis.
14.4
Shipping:
Contact Zhiefi Zu for sample processing.  All blood samples will be batched 
shipped to Dr. Anil Sood’s laboratory at M.D. Anderson Cancer Center in 
Houston, Texas. All samples will be de-identified by a number that is only 
recognizable by the Principal Investigator.
15.0
PROTOCOL COMPLIANCE
The attending physician and oncology nurse must see each patient prior to each study 
time point indicated.  All required interim and pre-treatment data should be available to 
the physician. The physician must make a toxicity grade. All study parameters required 
by protocol before each cycle of therapy must be documented.
16.0
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