Alternative Exercise Program to Improve Skeletal Muscle Function and Fatigue in Cancer Survivors
Phase: NA
Conditions: Breast Cancer
Sponsor: University of Vermont

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
 
Project Title: 
Version Date: 
Alternative exercise program to improve skeletal muscle function and fatigue in cancer survivors 
1-15-19 
 
 
NCT number: 
NCT02739620 
 
 
Principal Investigator:   
Michael J. Toth 
 
Grant Sponsor: 
National Cancer Institute 
Grant Number: 
R21 CA191532        
 
 
 
 
 

 
Lay Summary:  
Exercise training is effective at mitigating the negative health effects of cancer and its treatment and 
improving long-term prognosis, but there are substantial hurdles to disseminating exercise to the large, 
and rapidly growing cancer survivor population (~18 million by 2022). Clinical populations have 
traditionally participated in exercise primarily through facility-based programs (eg, cardiac and 
pulmonary rehabilitation). However, very few of these exist for oncology patients and such programs 
may not be feasible for both practical and clinical reasons; in particular, during chemotherapy, where 
logistical and clinical hurdles to participation are high, but when muscle adaptations likely evolve. 
Moreover, access to exercise facilities may be limited, particularly for patients living in rural communities 
(20% of US population), such as Vermont. Moreover, fatigue and other functional morbidities arising 
from cancer and its treatment deter participation. As positive results from randomized, controlled trials 
move exercise closer to standard of care in cancer survivors, a critical barrier to its broad dissemination 
will be the development of effective exercise modalities for patients who are underserved by facility-
based programs.  
Our long-term goal is to develop a clinically useful, exercise intervention that can serve as an 
alternative to facility-based programs, with the objectives of alleviating fatigue, forestalling disability and 
improving prognosis. Our objective in this application is to determine whether exercise training via 
neuromuscular electrical stimulation (NMES) has beneficial effects on skeletal muscle size and function 
in cancer patients. We hypothesize that NMES will improve skeletal muscle size, contractile function and 
oxidative capacity, based on our seminal observations in cancer patients that functional disability 
derives, in part, from deficits in skeletal muscle contractile protein and mitochondrial content and 
function, as well as our data showing that NMES counters such deficits. Our rationale underlying this 
proposal is that establishing proof-of-principle, mechanistic evidence for the utility of NMES to remediate 
these skeletal muscle deficits in cancer patients receiving treatment will provide a solid foundation upon 
which to support more definitive trials of the utility of NMES in the cancer survivor population.  
We will use data from cancer patients studied prior to and 8 weeks following completion of NMES or 
control intervention on lower extremity musculature, with muscle structure and function being measured 
across a range of anatomic levels. We focus on testing our hypotheses with cellular and organellar level 
measurements because they permit a more rigorous evaluation of the effects of NMES on muscle 
biology by circumventing limitations in the detection of exercise effects at the whole body or whole 
muscle level due to methodological shortcomings, subjective motivation and, specific to NMES, effects 
on neural activation. Determination of the utility of NMES to influence the quantity and functionality of 
contractile proteins and mitochondria is important, as detrimental adaptations in these parameters leads 
to muscle atrophy, weakness and increased fatigability, skeletal muscle phenotypes that are likely at the 
root of cancer-related fatigue and disability and, in turn, reductions in physical activity that negatively 
affect long-term prognosis. 
Successful completion of the proposed studies will provide mechanistic evidence for the utility of 
NMES to improve skeletal muscle size and function in cancer patients during treatment, which will 
support larger scale, randomized, control trials of its feasibility and efficacy. Specific to our investigative 
team, this will facilitate application of NMES to rural cancer survivors, a target population for this 
modality and one we are well-positioned to study. More broadly, development of NMES as an exercise 
modality in cancer patients could positively impact the oncology exercise rehabilitation field by providing 
a new, low-cost intervention that could extend the benefits of exercise to cancer patients underserved by 
facility-based training programs and during treatment, a time when facility-based programs are less 
feasible, but when detrimental muscle adaptations likely evolve. The history of NMES use within 
orthopedic and neurologic rehabilitation settings, its low-cost and the availability of FDA-approved 
devices for NMES and clinicians trained in its application (physical and occupational therapists), reduces 
logistical, financial and regulatory barriers to its broader repurposing for the cancer survivor population. 
 
 
Purpose:  
Exercise in cancer survivors is safe and has numerous health benefits (1-4). Less clear is how to 
disseminate the benefits of exercise to the large and growing number of cancer survivors (5, 6). In 
cardiac and pulmonary disease populations, this occurs primarily through facility-based programs. 

However, very few of these programs currently exist for cancer survivors and participation rates in other 
conditions are quite low (eg, 10-20% for cardiac rehab (7)). Participation may be further hindered in 
cancer survivors because of limited access to exercise facilities, particularly in rural populations (8), and 
disease/treatment-related side-effects, such as fatigue (9). Thus, alternatives to facility-based exercise 
programs are needed that effectively promote an exercise training response, integrate easily into 
outpatient and home environments, are easy to use and require minimal costs and equipment. 
Neuromuscular electrical stimulation (NMES) fulfills these criteria. An inexpensive (~$500), hand-
held NMES unit permits extracorporeal initiation of muscle contractions that can mimic resistance- or 
aerobic-type exercise (10), producing a training response similar to these modalities (11) with near 
comparable effects (12, 13). The non-volitional nature of NMES is also attractive, as cancer-related 
fatigue may deter motivation towards volitional exercise (9). NMES improves muscle size, strength and 
performance in older adults with chronic disease (14) and counteracts muscle atrophy coincident with 
disuse (15) and catabolic clinical conditions (16-18). Despite these beneficial effects, NMES has 
received almost no attention in cancer patients, where factors related to the disease (19, 20) and/or its 
treatment (21) may hinder exercise adaptations, although preliminary results from a case report (22) and 
small clinical trial (23) are encouraging. 
The proposed studies are designed to determine the effect of NMES on skeletal muscle in 
cancer patients receiving chemotherapy, with the expectation that our results will demonstrate 
salutary effects on muscle morphology and function. These findings would advance the oncology 
rehabilitation field by providing a solid, mechanistic evidence base to support the utility of NMES as 
a surrogate exercise modality during cancer treatment. Such evidence would reduce the risk for 
failure of this modality in more definitive, randomized, controlled trials in the broader cancer 
population.    
The proposed studies are innovative in seeking to develop effective exercise modalities for cancer 
survivors who are underserved by facility-based programs. They build on our seminal work describing 
fundamental cellular and sub-cellular deficits in skeletal muscle structure and function that contribute to 
disability in cancer survivors (24) by evaluating the utility of NMES to improve these same parameters. 
In this context, our experimental approach is also innovative in seeking to provide mechanistic evidence 
for the beneficial effects of NMES on skeletal muscle. We believe that this approach can economize the 
initial exploratory phase of developing new exercise modalities by testing the efficacy of an intervention 
to affect those skeletal muscle properties that are typically improved in response to exercise: size, 
contractility and oxidative function.  
Background, Preliminary Results and Hypothesis for Aim 1  
Cancer survivors often experience skeletal muscle weakness (25), due, in part, to atrophy resulting 
from cancer and its treatments (26). However, strength deficits exceed the loss of muscle (24, 27), due 
to intrinsic muscle contractile dysfunction, as our seminal work (24) showed that cancer (mostly lung) 
was associated with reductions in both slow-twitch, myosin heavy chain (MHC) I and fast-twitch, MHC II 
fiber contractility, which scaled to the whole muscle level. Whole muscle weakness, in turn, contributed 
to real-world disability, as it was associated with diminished walking performance (24). Our preliminary 
data show that functional deficits in MHC I and IIA fibers are apparent in women with breast cancer 
tested during chemotherapy similar to women with lung cancer from our prior work (24) and scale to the 
whole muscle level. In fact, contractile deficits tended to be greater in breast vs. lung cancer patients 
when compared to women without cancer. Our new data further show that muscle fiber atrophy and 
dysfunction develop during chemotherapy in lung cancer patients. Collectively, these results suggest 
both atrophy and intrinsic contractile deficiencies as determinants of reduced muscle functionality in 
breast cancer patients and identify treatment as a time when these phenotypes may evolve, 
emphasizing the need to identify interventions that counter muscle adaptations at this time. 
NMES improves muscle size and contractile function at the whole muscle level in other diseases 
(14). That NMES has effects in cancer patients is supported by one trial showing a trend toward 
increased whole muscle strength after 4 wks of stimulation in lung cancer patients (23), although it is 
unclear whether these improvements were due to enhanced neural activation (28) or durable changes in 
muscle fiber size and/or contractility. This is an important distinction, as the former would diminish 
following cessation of NMES, whereas the latter would provide more lasting functional benefits. Our new 
data suggest that NMES directly regulates muscle fiber size and function, as it counters both single fiber 
atrophy and functional deterioration in older adults following total knee arthroplasty, a period 

characterized by profound atrophy and dysfunction. These effects of NMES to prevent atrophy in MHC I 
fibers and cut atrophy in ~½ in MHC II fibers is remarkably similar to our data on the effects of classical 
training to prevent atrophy in lung cancer patients receiving treatment, suggesting NMES may function 
as a surrogate of classical training programs. Collectively, these data support the hypothesis that NMES 
will increase single skeletal muscle fiber contractile function and size in breast cancer patients 
compared to patients randomized to control intervention. Aim 1 will test this hypothesis. 
Background, Preliminary Results and Hypothesis for Aim 2  
Fatigue is a common side effect of cancer and its treatment, affecting a large majority of patients 
(29). It is multi-factorial in nature, comprising both central neural and periperal physiological adaptations 
(30). One peripheral muscle adaptation that may promote fatigue is reduced oxidative capacity (31). We 
recently showed, for the first time in humans, that cancer and its treatment are associated with 
mitochondrial rarefaction (24), which we have subsequently observed in breast cancer patients studied 
during chemotherapy. Further compounding reductions in mitochondrial content, cancer (32, 33) and 
chemotherapeutic agents used in breast cancer (34) have been shown to impair mitochondrial function 
in pre-clinical models. Mitochondrial loss and dysfunction during cancer treatment, therefore, may 
contribute to cancer-related fatigue and functional disability. 
NMES improves skeletal muscle oxidative function, with effects that rival those found with classic 
aerobic-type exercise training (12, 13). In fact, our preliminary data show that NMES can activate 
mitochondrial biogenesis and improve mitochondrial function. NMES use in patients for 5 wks following 
TKA not only prevented mitochondrial loss, but increased fractional content, and mitigated the effect of 
TKA to reduce mitochondrial function. Our new preliminary data show that reductions in ADP-stimulated 
OCR during treatment in lung cancer patients are attenuated by resistance training, suggesting that 
NMES may function similar to classical training to prevent mitochondrial functional decline in cancer 
patients during treatment. Collectively, these results support the hypothesis that: Skeletal muscle 
mitochondrial content and function will be increased by NMES compared to breast cancer patients 
randomized to control intervention. This hypothesis will be tested in Aim 2 of these studies. 
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Objectives:  
Our objective of this study is to determine whether exercise training via neuromuscular electrical 
stimulation (NMES) has beneficial effects on skeletal muscle size and function in cancer patients. We 
hypothesize that NMES will improve skeletal muscle size, contractile function and oxidative capacity, 
based on our seminal observations in cancer patients that functional disability derives, in part, from 
deficits in skeletal muscle contractile protein and mitochondrial content and function, as well as our 
preliminary data showing that NMES counters such deficits. To test this hypothesis, we propose two 
specific aims: 
Aim 1: Determine the effect of NMES on skeletal muscle fiber size and contractile function.  
We hypothesize that skeletal muscle fiber size and contractile function will be greater in cancer 
patients receiving treatment who are randomized to NMES compared to controls. 
 
Aim 2: Determine the effect of NMES on skeletal muscle mitochondrial content and function. 

We hypothesize that skeletal muscle mitochondrial content and function will be greater 
in cancer patients receiving treatment randomized to NMES compared to controls. 
 
Study Design:   
We will use a prospective, randomized controlled design, in which recently-diagnosed, breast cancer 
patients (40 to 75 yrs) will be recruited (see Appendices I-VI for recruitment materials/data collection 
sheets) and undergo Baseline Testing during the 1st cycle of neoadjuvant or adjuvant chemotherapy. 
Patients will then be randomized (1:1) to 8 wks of NMES or Attention control intervention (n=12/group; 
Treatment Phase), with stratification for age and adjuvant or neoadjuvant chemotherapy. Following 
completion of the intervention, they will undergo Post-intervention Testing. 
Baseline testing will include assessments of single muscle fiber size and mechanical function and 
mitochondrial content and function, as well as whole muscle size and contractile function and walking 
performance. Detailed descriptions of these assessments are provided below. 
Treatment Phase Volunteers randomized to both NMES and attention control groups will receive 
instruction to maintain or increase their physical activity according to the clinics usual standard of care. 
Both interventions are described below in detail.  
Post-Intervention Testing will occur in patients who complete the NMES program and controls and will 
include measurements identical to Baseline Testing, with post-training biopsies performed ≥3 d following 
NMES to eliminate any residual effects, per our usual protocol in other training studies that have been 
IRB-approved. Post-intervention testing will occur within ±14 d from the 8 week intervention point 
New methodology: Our study employs cellular and organellar level measurements of skeletal muscle 
structure and function. Although the methodology used in these studies is not new per se, it has not 
been used in the setting of exercise intervention trials in cancer patients. We feel that our approach is 
innovative in circumventing limitations in the detection of exercise effects at the whole body or whole 
muscle level due to methodological shortcomings, subjective motivation and, specific to NMES, effects 
on neural activation. This approach can economize the initial exploratory phase of developing new 
exercise modalities by more accurately characterizing the effects of such programs on those properties 
typically improved with exercise; namely, muscle size, contractility and oxidative function. 
Procedures:   
All of the procedures and interventions in this study are carried out solely for research purposes, as 
none are part of standard therapy/care in breast cancer patients. 
Primary outcomes include: skeletal muscle fiber cross-sectional area (CSA) and function and 
mitochondrial content, morphology and function. Secondary outcomes include: whole muscle 
size/function and 6 min walk performance and indices of chemotherapy-induced peripheral neuropathy 
(CIPN). Procedures that will be performed on volunteers to obtain these primary and secondary 
outcome measures are described below. 
Biopsy of the vastus lateralis (VL) will be performed, as used by our research group in a range of 
patient populations, including cancer patients (1), with the study leg chosen as the stronger leg in ½ of 
patients and the weaker leg in the other ½ so as not to bias adaptations based on minor functional 
asymmetries. Tissue will be proportioned for mechanical, immunohistochemical (IHC), mitochondrial 
respiratory and electron microscopy (EM) measurements, with remaining tissue frozen in liquid N2. The 
VL was chosen because of its importance in determining functional disability (2) and its structural and 
functional deficiencies in cancer patients previously described by our laboratories (1). 
Single fiber function, including tension, velocity and power, will be measured on chemically-skinned, 
muscle fiber segments (n≈25/subject/biopsy) using isotonic load clamps, as described by us (3), with 
data available on MHC I and IIA fibers, the two most prevalent fiber types in human muscle (1, 4). 
Single fiber cross-sectional area (CSA) will be measured by IHC, as we have described (1, 3), with 
minor modifications to permit assessment of all MHC isoforms, as described (5).  
Whole muscle contractile function will be measured, as described by us (6). Maximal peak isometric 
(70°, 90°) and isokinetic knee extensor torque (60 and 180°/sec) will be adjusted for thigh muscle CSA 
to account for variation in muscle size. Additionally, muscle fatigue will be assessed following repeated 

(n=24) isometric contractions. Briefly, 24 maximal voluntary isometric contractions (2 min of intermittent 
contractions at 70º), following a duty ratio of 3 seconds of contraction and 2 seconds of rest. Fatigue will 
be defined as the average peak torque from the final 3 contractions divided by the highest peak torque 
achieved prior to initiation of the fatigue protocol (ie, Isometric knee extensor strength determination 
prior to the fatigue measure). 
Thigh muscle size will be measured by dual energy x-ray absorptiometry, as described by us (1). 
Additionally, anthropometrics and body mass will be assessed. Height will be measured without shoes, 
using a stadiometer to the nearest 0.5cm. Weight will be obtained from the DEXA estimate. BMI will be 
calculated as weight (kg)/height(m2). 
6 min walk test will be performed, as described (1), to assess changes in physical functional 
capacity. 
Single legged stance will be performed to test balance in each leg separately. The participants place 
their hands on their hips then raise the 1 foot off the floor. Stance is timed until the raised foot touches 
the floor, the stationary foot moves, the raised foot touches the stationary leg or the hands are taken 
from their starting position. It is repeated three times and the best value is used. If stance exceeds 30 
seconds the test will be stopped at that time. 
Accelerometry will be performed, as described (6), to monitor weight-bearing activity levels, which 
can be used to account for possible variation in muscle use between groups (Appendix VII). 
Questionnaires (provided in Appendix VIII) will be provided to assess fatigue symptoms (Fatigue 
Symptom Index), physical activity level (Stanford Brief Physical Activity Questionnaire), general 
health/well-being (MOS SF-36) and CIPN (EORTC CIPN 20). 
Nerve conductions studies (NCS) will include the sural, peroneal and tibial nerves bilaterally and are 
the best measure of large nerve fiber function that is affected by both exercise and chemotherapy. NCS 
take about ten minutes and record electrical signal after providing a very mild electrical stimulus to the 
skin. The amplitude, distal latency, and conduction velocity will be recorded for each nerve. Study of 
both legs require a total of 15-20 stimulus applications, some of which are too weak to be felt. 
Clinical neuropathy assessment: The Utah Early Neuropathy Scale (UENS) is a lower extremity 
examination performed by a neurologist that tests different modalities of strength, sensation and reflexes 
to detect neuropathy. It examines great toe strength, pin sensation, allodynia, vibratory sensation and 
Achilles reflexes in both legs. 
 
Treatment Phase 
     Volunteers randomized to both the NMES intervention and control groups will receive instruction to 
maintain or increase their physical activity according to the clinics usual standard of care.  
NMES will be carried out bilaterally on the quadriceps using a portable stimulation device (EMPI 
Continuum or 300PV). Study personnel will teach volunteers to use the NMES device and provide 
detailed directions for its use (Appendix IX). Briefly, two adhesive electrodes will be affixed to anterior 
surface of each thigh: ~1 cm distal to the inguinal crease and ~5 cm proximal to the patella, with the leg 
maintained in isometric conditions by placing a bolster under the knees and using ankle weights. 
Symmetrical, biphasic pulses (400 µs duration at 50 Hz) will be used, with a duty cycle of 25% (10 s on, 
30 s off) at stimulation intensities sufficient to cause visible muscle contractions below pain threshold. 
NMES sessions will occur 5 d/wk for 1 hr/d (two 30 min or one 60 min session) for 8 wks. This regimen 
(lower duty cycle and 60 min/d) differs slightly from that put forth in the grant proposal in lieu of 
reviewer’s comments on the resubmission and consultation with out co-investigator (Dr. Stevens-
Lapsley), as well as comments from volunteers in our VCC/LCCRO Pilot Project Grant, where 
volunteers suggested that we offer shorter sessions, as finding time for longer sessions was problematic 
for women with family and work commitments. We will monitor adherence to the NMES program 
covertly using the compliance monitoring feature built in to the NMES device software. Additionally, 
volunteers will self-report compliance, stimulation intensity and muscle soreness/side effects (Appendix 
VIII and X) and these reports will be reviewed during weekly phone contacts by study personnel. Finally, 
we will assess acceptability of the program using a questionnaire. These measures are taken to inform 
future RCTs if our hypotheses are supported. 

Attention control patients will not receive an NMES device. They will receive weekly phone calls to 
discuss measurements of leg muscle soreness to standardize the amount of interaction with study 
personnel to the NMES group.  
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cross-bridge formation and kinetics. J Appl Physiol 114, 858-868 
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3. Callahan, D. M., Miller, M. S., Sweeny, A. P., Tourville, T. W., Slauterbeck, J. R., Savage, P. D., Maughan, D. W., Ades, P. 
A., Beynnon, B. D., and Toth, M. J. (2014) Muscle disuse alters skeletal muscle contractile function at the molecular and 
cellular levels in older adult humans in a sex-specific manner. J Physiol 592, 4555-4573 
4. Callahan, D. M., Tourville, T. W., Miller, M. S., Hackett, S. B., Sharma, H., Cruickshank, N. C., Slauterbeck, J. R., Savage, 
P. D., Ades, P. A., Maughan, D. W., Beynnon, B. D., and Toth, M. J. (2015) Chronic disuse and skeletal muscle structure in 
older adults: sex differences and relationships to contractile function. Am J Physiol Cell Physiol 308, C932-C943 
5. Fry, C. S., Noehren, B., Mula, J., Ubele, M. F., Westgate, P. M., Kern, P. A., and Peterson, C. A. (2014) Fibre type-specific 
satellite cell response to aerobic training in sedentary adults. J Physiol 592, 2625-2635 
6. Toth, M. J., Shaw, A. O., Miller, M. S., VanBuren, P., LeWinter, M. M., Maughan, D., and Ades, P. A. (2010) Reduced knee 
extensor function in heart failure is not explained by inactivity. Int J Cardiol 143, 276-282 
 
Surveys/Questionnaires:  
The Fatigue Symptom Inventory (FSI; Appendix VII) has been tested in several cancer patient 
populations and is a 14-item self-report of severity, frequency and pattern of fatigue. An 11 point scale is 
used (0=not at all fatigued; 10=as fatigued as I could be). Frequency is measured in numbers of days in 
the past week. Interference is measured on an 11 point scale (0=interference none of the day; 
10=interference the entire day). A mean score of ≥ 3 across the three-item FSI severity composite has 
been established as a cutoff for clinically significant cancer-related fatigue. 
Statistical Analysis Plan:  
Our primary goal is to assess the effect of NMES on: single fiber tension (force/CSA), velocity and CSA 
and mitochondrial content and ADP-stimulated oxygen consumption rate. A general linear mixed model 
will be used, with treatment group as between-subject and time as within-subject effects. A random 
effect will be included to account for clustering of observations within subjects (ie, fibers within each 
subject), as described (1), with the model conceptualized as a multi-level analysis with single 
fiber/organellar-level outcomes comprising level 1 variables and person-level covariates comprising 
level 2 variables (2). Covariates (eg, stage, chemotherapeutics, and activity level) can be included in the 
model as level 2 variables to control for potential confounders that differ by group. Whole muscle size 
and function and 6 min walk performance will be used in secondary analysis to evaluate whether 
changes in myofilament or mitochondrial content or function scale to variation in tissue-level or whole 
body function or size, as we have previously observed that molecular- and organellar-level function 
scale to the tissue and whole-body level in cancer (3), aging (4) and chronic disease (5). 
For Aim 1, based on whole muscle results in cancer patients (3, 6), other diseased populations (7, 8) 
and our preliminary data, we anticipate that volunteers randomized to NMES will have greater single 
muscle fiber tension (20%) and CSA (20%) versus controls. We focused on these variables because 
they represent the two most disabling effects of cancer on muscle contractility: weakness and atrophy 
(3, 9). We would need n=12/group to detect these differences between groups (power=90% and 
significance of 5%). Of note, we will likely have greater improvements in contractile velocity, per our 
preliminary data, which should further increase aggregate muscle power output and functionality and is 
readily detectable with this sample size. For Aim 2, based on our preliminary data showing the ability of 
NMES to improve mitochondrial content and function in the context of a profoundly atrophyic stimulit (ie, 
knee replacement surgery), we expect that patients randomized to NMES will have greater 
mitochondrial content (50%) and function (40%). Our sample size is driven by detecting changes in 
mitochondrial content, which would require n=12/group with a power of 90% and a significance of 5%. 
Using this sample size, our minimal detectable differences for changes in mitochondrial function would 
be 14%. We have not performed sample size estimates on secondary outcomes because of the 
exploratory nature of these studies, but also because it is likely that we will either not be able to detect 
effects at this anatomic level because of confounding factors or we will detect effects at this level that 
are unrelated to the effects of NMES to improve skeletal muscle size and/or function (eg, enhanced 
neural activation related to NMES training improves whole muscle strength). This was a primary impetus 

for our studies to evaluate the effects of NMES at the cellular/organellar level. However, we will evaluate 
these outcomes nonetheless, as they will provide important preliminary data for future trials if our 
hypotheses are supported by our results. 
1. Toth, M. J., Miller, M. S., VanBuren, P., Bedrin, N. G., LeWinter, M. M., Ades, P. A., and Palmer, B. M. (2012) Resistance 
training alters skeletal muscle structure and function in human heart failure: effects at the tissue, cellular and molecular 
levels. J Physiol 590, 1243-1259 
2. Hox, J. J. (2002) Multilevel Analysis: Techniques and Applications., Lawrence Erlbaum Associates, Inc., Mahwah, NJ 
3. Toth, M. J., Miller, M. S., Callahan, D. M., Sweeny, A. P., Nunez, I., Grunberg, S. M., Der-Torossian, H., Couch, M. E., and 
Dittus, K. (2013) Molecular mechanisms underlying skeletal muscle weakness in human cancer: reduced myosin-actin 
cross-bridge formation and kinetics. J Appl Physiol 114, 858-868 
4. Miller, M. S., Bedrin, N. G., Callahan, D. M., Previs, M. J., Jennings, M. E., Ades, P. A., Maughan, D. W., Palmer, B. M., and 
Toth, M. J. (2013) Age-related slowing of myosin actin cross-bridge kinetics is sex specific and predicts decrements in whole 
skeletal muscle performance in humans. J Appl Physiol 115, 1004-1014 
5. Miller, M. S., Callahan, D. M., and Toth, M. J. (2014) Skeletal muscle myofilament adaptations to aging, disease and disuse 
and their effects on whole muscle performance in older adult humans. Front Physiol 5, 369 
6. Maddocks, M., Lewis, M., Chauhan, A., Manderson, C., Hocknell, J., and Wilcock, A. (2009) Randomized controlled pilot 
study of neuromuscular electrical stimulation of the quadriceps in patients with non-small cell lung cancer. J Pain Symptom 
Manage 38, 950-956 
7. Vivodtzev, I., Debigaré, R., Gagnon, P., Mainguy, V., Saey, D., Dubé, A., Paré, M.-È., Bélanger, M., and Maltais, F. (2012) 
Functional and muscular effects of neuromuscular electrical stimulation in patients with severe copd: A randomized clinical 
trial. CHEST 141, 716-725 
8. Quittan, M., Wiesinger, G. F., Sturm, B., Puig, S., Mayr, W., Sochor, A., Paternostro, T., Resch, K. L., Pacher, R., and 
Fialka-Moser, V. (2001) Improvement of thigh muscles by neuromuscular electrical stimulation in patients with refractory 
heart failure: a single-blind, randomized, controlled trial. Am J Phys Med Rehabil 80, 206-214 
9. Der-Torossian, H., Couch, M. E., Dittus, K., and Toth, M. J. (2013) Skeletal muscle adaptations to cancer and its treatment: 
their fundamental basis and contribution to functional disability. Crit Rev Eukaryot Gene Expr 23, 283-297 
 
Risks/Benefits:  
Potential risks: Below we have highlighted those procedures that have anything greater than negligible 
risk to the volunteers’ health for each phase of the study. 
 
Baseline/Post-intervention Testing: There is a minimal risk for hematoma or infection from the muscle 
biopsy. All equipment used will be sterile and every precaution will be taken to reduce the possibility of 
infection. Risks associated with the muscle biopsy procedure include excessive bleeding, persistent 
numbness or infection. Regarding bleeding risk, we will exclude any patients taking anti-coagulant 
medication or with known coagulopathies. All of these risks are well below 1% (81) and our laboratory 
has never had an adverse event related to the muscle biopsy procedure. Although evidence is limited, 
there is some evidence that the rhythmic muscle contraction induced by the use of NMES could 
increase the risk of dislodging a lower extremity blood clot.  However, several published reports show 
that NMES reduces the risk of developing such clots. Thus, the risk of NMES causing or dislodging 
such a clot is minimal, but difficult to measure exactly. There is a risk for having an allergic reaction to 
the antiseptic that we use to clean the site of the biopsy.  The risk for such a reaction is relatively low 
(1% or less).  Finally, the adhesive strips use to close the biopsy incision could cause irritation to the 
skin in individuals with sensitive skin, which could cause a rash or blister.  The muscle biopsy will be 
performed by trained, qualified clinicians in a closely controlled, medical environment. There is risk for 
muscle soreness or damage from whole muscle functional testing. Appropriate warm up exercises will 
be performed to prevent muscle injury. The DEXA scan exposes the volunteers to x-rays, although the 
total exposure is equivalent to approximately 1 d of normal daily background radiation. 
Anti-coagulant therapy/muscle biopsy: Stage 3 and 4 cancer patients being treated at University of 
Vermont Medical Center typically receive prophylactic anti-coagulant therapy to prevent deep vein 
thrombosis. Accordingly, patients will have to discontinue this therapy just prior to the biopsy to limit the 
possibility of forming a hematoma or excessive bleeding during the biopsy. The following schemes detail 
the types of possible medications that could be taken and the discontinuation and resumption 
procedures for each (note: these schemes have been approved by Dr. Chris Holmes, who oversees this 
treatment program for patients in the Division of Hematology/Oncology):  
Apixiban (Eliquis)  
Prophylactic dose:  2.5 mg BID 
Treatment dose:  10 mg BID for 7 days then 5mg BID 
 
Discontinue: 48 hours prior to biopsy 

Resumption:  Day following the biopsy 
 
Rivaroxaban (Xarelto) 
Prophylactic dose:  10mg  
Treatment dose:   15mg BID x 21 days than 20 mg daily 
 
Discontinue: 48 hours prior to biopsy 
Resumption:  Day following the biopsy 
 
Enoxaparin (Lovenox) 
Prophylactic dose:  40 mg subcutaneous daily 
 
Discontinue: If taken in the morning do not take am dose day of biopsy 
If taken in the evening, hold evening dose 
Resumption: Day following the biopsy if taken in the am 
Evening after the muscle biopsy if taken in the evening 
 
Treatment dose:  1mg/kg BID 
 
Discontinue: Hold dose evening prior to biopsy 
Resumption:  Evening after the muscle biopsy 
 
Dalteparin (Fragmin) 
Prophylactic dose:  5,000 units subcutaneous daily 
Treatment dose:  200 units/kg daily first month than 150 units/kg daily 
 
 
Discontinue: If taken in the morning do not take am dose day of biopsy 
If taken in the evening, hold evening dose 
Resumption: Day following the biopsy if taken in the am;   
Evening after the muscle biopsy if taken in the evening 
 
UF Heparin 
Prophylactic dose:  5000 units subcutaneous TID 
Treatment dose:  Variable 
 
Discontinue: Day prior to biopsy 
Resumption:  Day following the biopsy 
 
Aspirin or NSAIDs – Discontinue 5 days prior 
Resume day following biopsy 
 
NMES intervention:  NMES is a generally safe procedure, delivered in this study by an FDA-approved 
device. Although evidence is limited, some groups have suggested that NMES could increase the risk of 
dislodging a deep vein thrombosis (DVT), which may have serious health consequences. However, 
several published reports show that NMES significantly reduces the risk of developing DVTs and we will 
actively exclude any individual with a known coagulopathy. Because of the location of the stimulating 
electrodes (upper leg), the risk of NMES dislodging a DVT is likely minimal. Electrical stimulations 
associated with NMES of the upper leg may be sensed by cardiac defibrillators as an arrhythmia, 
causing the device to discharge inappropriately. Thus, consistent with current clinical practice 
guidelines, we will exclude any volunteers that currently have an implanted cardiac defibrillator or 
pacemaker. 
     Patients will be encouraged to adjust stimulation to a tolerable level and will have full control over the 
stimulator to continue to make adjustments as necessary. During the first couple of NMES sessions, 
muscle soreness may occur. The level of fatigue and/or soreness will be similar to that which occurs 
following a standard exercise training session and will dissipate over time as the volunteer’s muscles 
become accustomed to the electrically-stimulated contractions (ie, they become trained). Nonetheless, 

in response to concerns of the NIH reviewers, we have instituted a regimen of assessing muscle pain 
each week using a hand-held pressure algometer, with results being reviewed with volunteers during 
weekly phone contacts. Volunteers will be instructed on how to assess muscle soreness manually at 
standardized points along their quadriceps. Briefly, the volunteer will provide 2 kg/cm2 of pressure using 
the algometer at each site, which will provide mild pressure over 1 cm2-size of rubber algometer probe 
that will be below pain threshold. If muscle soreness related to the NMES is present, there may be mild 
soreness/pain at the site of algometer testing and the volunteer will note her level of discomfort using 
the Wong pain scale (0-10). Any level of discomfort greater than 6, or if the patient reports muscle 
soreness that hinders simple activities of daily living, such as walking, the research coordinator will 
contact the PI for referral to the Safety Officer. The Safety Officer will then follow up with the patient by 
phone (or in person, if deemed necessary) to assess the volunteer’s level of discomfort and whether she 
should continue in the study. In our past experience with exercise training and NMES, there is some 
level of discomfort expected as the muscle is trained. However, in all cases, muscle soreness has not 
been sufficient that volunteers have chosen to discontinue the study or that it substantially hinders daily 
activities.  
 
Benefits: The direct benefit of the research to volunteers is not immediately known because of the 
paucity of studies that have evaluate NMES in cancer survivors. NMES may improve skeletal muscle 
structure or function and, in turn, improve physical functional capacity. Because of this, patients may 
experience improved physiological capacity, which could reduce fatigue and disability. If NMES is shown 
to have beneficial effects on skeletal muscle, further research and application of the technique to cancer 
patients may help to extend the benefits of exercise to cancer survivors not able to participate in facility-
based exercise training programs.  
More broadly, the results of these studies may impact supportive care regimens for cancer patients in 
the future. Our studies will provide seminal information regarding the effects of NMES on skeletal 
muscle at the cellular and organellar levels. If successful, our results will provide a solid, mechanistic 
evidence base on which clinical trials designed to further examine the utility of NMES in cancer patients 
can be launched. Because of the mechanistic nature of our data, our findings may also be used to guide 
the development and refinement of clinical rehabilitation interventions designed to counter detrimental 
skeletal muscle adaptations in cancer patients, as guidelines for oncology rehabilitation are still in the 
early stage of development. Additionally, because we will be obtaining evidence on the mechanisms 
whereby NMES is affecting skeletal muscle structure and function at the fundamental molecular/cellular 
level, our data could stimulate further basic science research into the mechanisms of action of NMES 
and how stimulation of these signaling pathways counteracts the effects of cancer and its treatment. 
Thus, our work may identify the mechanisms whereby cancer and its treatment impact skeletal muscle 
size and function.  
Overall, the risks to general health and well-being of the volunteers are quite minimal and, based on the 
utility of NMES in other diseased populations to increase muscle size and functionality, the likelihood 
that NMES will improve physiological function in patients is quite high. For these reasons, and together 
with the advances in knowledge to be gained from these studies, we believe that the risks of this study 
are reasonable given the potential gains in functionality for the patients and knowledge to improve 
exercise interventions for future cancer survivors. 
Therapeutic Alternatives:   
NMES seeks to provide an exercise training stimulus to volunteers to help maintain skeletal muscle size 
and functionality. During treatment, there is generally not an alternative exercise program available, as 
our institutional oncology rehabilitation program does not typically begin until after treatment is complete. 
This lack of therapeutic alternatives during treatment was a primary impetus for undertaking these 
studies. Volunteers can chose to exercise on their own, however, and not participate in the current 
study. 
Data Safety and Monitoring:   
Our study is a clinical trial, but not a phase III clinical trial. Thus, pursuant to NIH regulation, we will 
establish a formal Data Safety Monitoring Plan, which will provide additional oversights to further protect 
against risk to safety and confidentiality. 

     The PI (Toth) and Dr. Dittus will monitor the safety of the research procedures for this study. Dr. 
Toth will be available on-site for all major experimental procedures (eg, muscle biopsy) that might 
reasonably be expected to pose safety concerns for volunteers. In this context, the PI will be readily 
available to monitor volunteer safety throughout the study. If an event occurs that affects participant 
safety, the PI and/or Dr. Dittus will alert the Safety Officer (Dr. Michelle Sowden), who will adjudicate the 
event with respect to its severity, expectedness and relatedness to participation in the study according 
to the aforementioned criteria. Because numerous clinical trials in our laboratory have demonstrated the 
safety of this regimen of testing in patients from a broad range of clinical backgrounds (eg, heart failure 
patients, cancer survivors, healthy elderly), we expect minimal problems related to testing. NMES is 
generally a very safe intervention, having been used in a variety of acute and chronic conditions, from 
heart failure patients awaiting transplant to ICU patients. Additionally, we will actively monitor volunteers 
at regular intervals (weekly phone calls) to assure that no problems develop. Thus, we do not feel that it 
is reasonable to incorporate "stoppage criteria" for the overall study. Instead, the Safety Officer will 
decide whether an individual participant should continue with the study following occurrence of any 
adverse events or unanticipated problems taking into consideration what is in the best interest of that 
individual, including instances of undue muscle soreness related to the NMES device. 
 
Adverse Event and Unanticipated Problem (UAP) Reporting:  
Adverse events will be reported by one of 3 mechanisms. First, the UVM/UVM Medical Center 
Committee for Human Subject Research Adverse Event Reporting Form. Report of any event will be 
forwarded to the office of the Committee for Human Research in the Medical Science (CHRMS) within 2 
days of the PI learning about the event. Reporting adverse events will be the responsibility of the PI. The 
CHRMS will determine whether additional reporting requirements are indicated. Second, the Patient 
Safety Reporting system (SAFE) through UVM Medical Center can also be used, which may be initiated 
by clinical research center staff or study personnel. These forms will be forwarded within 3 days to the 
PI, UVM Medical Center Risk Management Office, CHRMS and other appropriate agencies, as 
indicated by the nature of the report. Finally, the UVM Medical Center Medication/IV Event Report Form, 
with distribution and timing as noted above. This latter mechanism might be used with events related to 
blood sampling or other invasive procedure, such as the biopsy. Reviews of protocol specific adverse 
events will be performed no less than annually. Additionally, any adverse event that occurs will be 
forwarded to the PI for reporting to the Human Subject Research Protection Office within 1 week of 
occurrence. Of note, these protections against risk include both physical risks to the volunteers, as well 
as risks associated with any breach in confidentiality. 
On an annual basis, Drs. Toth and Dittus will assess data being gathered and safety of volunteers to 
assess the pattern or frequency of events to identify occurrence of any event or problem that 
significantly alters the safety profile of the procedures being performed, unless occurrence of a serious 
adverse event or unanticipated problem necessitates re-evaluation of the expected risk of the study 
procedures at an earlier time point. Additionally, Dr. Toth will evaluate data collection and storage to 
ensure the confidentiality of data and quality. Each of these evaluations will be followed by reports of 
study progress and patient safety to the University of Vermont Committee on Human Research in the 
Medical Sciences via yearly progress reports and to the appropriate NCI program officer. The report will 
include information regarding study status, participant information and safety information. This report will 
also be forwarded to the Safety Officer for his review. 
Withdrawal Procedures:  
Patients will be removed from study if they are found to have cancer progression during the study, if 
they experience a hospitalization greater than 48 hrs, if they require dexamethasone therapy for longer 
than 5 d, if they are non-compliant with research personnel instruction or if continued participation would 
not be in the best interest of the volunteer’s health. 
Sources of Materials:   
An individual research record will be kept on each volunteer in compliance with HIPAA standards. This 
record will contain identifying data, demographic information and results from all clinical research 
measurements and evaluations. Data will be gathered from the volunteer and her medical records after 
she freely gives consent. The results of all testing will be kept confidential. In addition, skeletal muscle 
tissue samples will be taken and will be used for measurement of muscle size, structure and function. All 

materials gathered in conjunction with the proposed studies will be used for research purposes only and 
will be available only to research personnel working on these studies, who have obtained proper training 
in human subjects research and privacy protection. All materials collected for this study will be used for 
research purposes only. 
 
Device (s): 
 
 
The interventional device used in this trial: EMPI Continuum complete electrotherapy systems have both 
received FDA approval for retarding disuse-related atrophy, which we believe is one of the primary 
mechanisms whereby muscle adaptations evolve in cancer survivors. That is, fatigue and weakness 
associated with chemotherapy cause patients to be less physically active, which, in turn, causes skeletal 
muscle fiber atrophy and weakness and mitochondrial rarefaction and dysfunction. 
Is it FDA approved: 
Yes. It is approved to mitigate muscle atrophy/dysfunction associated with muscle disuse, which we 
hypothesize is one of the major underlying precipitants of muscle changes in cancer patients during 
treatment, as others have characterized profound reductions in muscle use with cancer treatment (1). 
1. Ferriolli E, Skipworth RJE, Hendry P, Scott A, Stensteth J, Dahele M, et al. Physical activity monitoring: a responsive and 
meaningful patient-centered outcome for surgery, chemotherapy, or radiotherapy? J Pain Symptom Manage. 2012;43:1025-
35. 
Risk assessment:  
The device (and similar devices) has been used extensively in the orthopedic and neural rehabilitation 
settings by physical and occupational therapists and in numerous disease states (heart failure, chronic 
obstructive pulmonary disease, knee replacement) to improve muscle size and function in clinical trial 
settings. Thus, NMES is a generally safe procedure with a long safety record. Although evidence is 
limited, some have suggested that NMES could increase the risk of dislodging a deep vein thrombosis 
(DVT) because of the rhythmic muscle contractions induced by the electrical stimulation. However, 
several published reports show that NMES significantly reduces the risk of developing DVTs. In fact, the 
device we are using is FDA-approved for prevention of DVT of the calf muscles immediately following 
surgery. Moreover, we will actively exclude any individual with a known coagulopathy or DVT. Because 
of the location of the stimulating electrodes (upper leg), the risk of NMES dislodging a DVT is likely 
minimal. There are also several case reports that NMES may be sensed by cardiac defibrillators as an 
arrhythmia, causing the device to discharge inappropriately. Thus, consistent with current clinical 
practice guidelines, we will exclude any volunteers that currently have an implanted cardiac defibrillator 
or pacemaker. Finally, during the first couple of NMES sessions, muscle soreness may occur. Thus, we 
will actively monitor muscle soreness in volunteers to prevent undue discomfort. 
 
Subject Selection:  
We propose to study NMES in breast cancer patients receiving chemotherapy for several reasons. First, 
breast cancer is the most prevalent cancer in women and the second most prevalent cancer overall, 
making our results broadly relevant. Second, women show higher disability rates than men (1, 2), which 
may relate to their more detrimental skeletal muscle molecular and cellular functional adaptations that 
we have characterized with aging (3) and muscle disuse (4, 5). Third, breast cancer patients show 
structural and functional muscle changes similar to those we have found in other cancers that relate to 
disability (6). Finally, we include a broad age range of patients because we have observed phenotypic 
adaptations in younger patients (mitochondrial rarefaction) and prior reports suggest that cancer and its 
treatment cause the greatest functional deficits in younger patients (7), arguing that younger women 
may benefit from NMES. We exclude “old” and “oldest old” populations (>75 yrs) because of their higher 
rates of co-morbidities, which could affect the ability to detect NMES effects. 
We chose to examine effects of NMES during chemotherapy for several reasons. This is a logical time 
for exercise intervention to counteract concomitant reductions in habitual physical activity (8-10) and 
their physiological sequelae (11). Support of muscular activity and maintenance of physiological reserve 
may be critical to improving long-term outcomes, as inactivity is associated with increased mortality in 
breast cancer patients (12, 13). Moreover, in light of our new preliminary data in cancer survivors, this 
period is characterized by reductions in skeletal muscle size and function and classical exercise training 
can counteract these adaptations, with the latter effects being similar to those observed with NMES in 

other populations. In this context, our study promotes a more proactive, preventative approach to 
functional deterioration in cancer patients, which, by maintaining muscle size and function, may lead to 
greater functional and long-term health benefits (14). 
1. 
Hardy, S. E., Allore, H. G., Guo, Z., and Gill, T. M. (2008) Explaining the effect of gender on functional transitions in older 
persons. Gerontology 54, 79-86 
2. 
Newman, A. B., and Brach, J. S. (2001) Gender gap in longevity and disability in older persons. Epidemiol Rev 23, 343-355 
3. 
Miller, M. S., Bedrin, N. G., Callahan, D. M., Previs, M. J., Jennings, M. E., Ades, P. A., Maughan, D. W., Palmer, B. M., 
and Toth, M. J. (2013) Age-related slowing of myosin actin cross-bridge kinetics is sex specific and predicts decrements in 
whole skeletal muscle performance in humans. J Appl Physiol 115, 1004-1014 
4. 
Callahan, D. M., Miller, M. S., Sweeny, A. P., Tourville, T. W., Slauterbeck, J. R., Savage, P. D., Maughan, D. W., Ades, P. 
A., Beynnon, B. D., and Toth, M. J. (2014) Muscle disuse alters skeletal muscle contractile function at the molecular and 
cellular levels in older adult humans in a sex-specific manner. J Physiol 592, 4555-4573 
5. 
Callahan, D. M., Tourville, T. W., Miller, M. S., Hackett, S. B., Sharma, H., Cruickshank, N. C., Slauterbeck, J. R., Savage, 
P. D., Ades, P. A., Maughan, D. W., Beynnon, B. D., and Toth, M. J. (2015) Chronic disuse and skeletal muscle structure in 
older adults: sex differences and relationships to contractile function. Am J Physiol Cell Physiol 308, C932-C943 
6. 
Toth, M. J., Miller, M. S., Callahan, D. M., Sweeny, A. P., Nunez, I., Grunberg, S. M., Der-Torossian, H., Couch, M. E., and 
Dittus, K. (2013) Molecular mechanisms underlying skeletal muscle weakness in human cancer: reduced myosin-actin 
cross-bridge formation and kinetics. J Appl Physiol 114, 858-868 
7. 
Kroenke, C. H., Rosner, B., Chen, W. Y., Kawachi, I., Colditz, G. A., and Holmes, M. D. (2004) Functional impact of breast 
cancer by age at diagnosis. J Clin Oncol 22, 1849-1856 
8. 
Courneya, K. S., and Friedenreich, C. M. (1998) Relationship between exercise during treatment and current quality of life 
among survivors of breast cancer. J Psych Oncol 15, 35-57 
9. 
Ferriolli, E., Skipworth, R. J. E., Hendry, P., Scott, A., Stensteth, J., Dahele, M., Wall, L., Greig, C., Fallon, M., Strasser, F., 
Preston, T., and Fearon, K. C. H. (2012) Physical activity monitoring: a responsive and meaningful patient-centered 
outcome for surgery, chemotherapy, or radiotherapy? J Pain Symptom Manage 43, 1025-1035 
10. Pinto, B. M., Trunzo, J. J., Reiss, P., and Shiu, S.-Y. (2002) Exercise participation after diagnosis of breast cancer: trends 
and effects on mood and quality of life. Psycho-Oncology 11, 389-400 
11. Lakoski, S., Barlow, C., Koelwyn, G., Hornsby, W., Hernandez, J., DeFina, L., Radford, N., Thomas, S., Herndon, J., II, 
Peppercorn, J., Douglas, P., and Jones, L. (2013) The influence of adjuvant therapy on cardiorespiratory fitness in early-
stage breast cancer seven years after diagnosis: the Cooper Center Longitudinal Study. Breast Cancer Res Treat 138, 
909-916 
12. Holmes, M. D., Chen, W. Y., Feskanich, D., Kroenke, C. H., and Colditz, G. A. (2005) Physical activity and survival after 
breast cancer diagnosis. JAMA 293, 2479-2486 
13. Irwin, M. L., McTiernan, A., Manson, J. E., Thomson, C. A., Sternfeld, B., Stefanick, M. L., Wactawski-Wende, J., Craft, L., 
Lane, D., Martin, L. W., and Chlebowski, R. (2011) Physical activity and survival in postmenopausal women with breast 
cancer: results from the Women's Health Initiative. Cancer Prev Res 4, 522-529 
14. Dittus, K. L., Lakoski, S. G., Savage, P. D., Kokinda, N., Toth, M. J., Stevens, D., Woods, K., O'Brien, P., and Ades, P. A. 
(2015) Exercise-based oncology rehabilitation: leveraging the cardiac rehabilitation model. J Cardiopulm Rehabil Prev 35, 
130-139 
Number of Subjects:   
We anticipate enrolling and completing testing on n=24 patients. We will recruit 28 volunteers with the 
anticipation of a dropout rate of ~15%. This is a reasonable dropout rate considering that, in our 
experience with other clinical populations (eg, heart failure patients, advanced stage knee osteoarthritis 
patients) we have had minimal dropouts during facility-based exercise interventions (<5%) that pose a 
greater burden on volunteers than the home-based NMES intervention in the current study. 
Inclusion/Exclusion Criteria:  
Patients will be considered for study if they are/have/will: 1) 40-75 years of age; 2) stage I, II or III breast 
cancer; 3) receive neoadjuvant or adjuvant chemotherapy and 4) a body mass index <38 kg/m2. 
Patients will be excluded if they have/had: 1) a prior history of cancer that required chemotherapy, 
excluding non-melanoma skin cancer; 2) autoimmune, vascular or neuromuscular disease that could 
alter skeletal muscle (eg, rheumatoid arthritis, peripheral arterial disease); 3) prior knee or hip 
replacement; 4) an implanted cardiac defibrillator or pacemaker; 5) a known coagulopathy, current lower 
extremity DVT or are taking anti-coagulant therapy (patients taking prophylactic anti-coagulation therapy 
are eligible if they discontinue this therapy according to the schemes detailed in the Risks/Benefits 
section) or 6) oral corticosteroid medication for non-cancer indications, excluding inhaled or topical 
formulations. We will exclude women who report being highly active prior to diagnosis (Stanford Brief 
Activity Survey), as these individuals may be less responsive to NMES (ie, ceiling effect), though this is 
likely to be a small fraction (<10%) of the overall population. 
Inclusion of Minorities and Women:.  
Inclusion of Women 

     This study will include only women. The rationale for this decision is based on our choice to study 
women with breast cancer, as detailed above in the Subject Selection section. Briefly, this decision was 
based partially on the fact that breast cancer is the second most prevalent type of cancer in the US, but 
also on work by our laboratory showing marked skeletal muscle structural and functional deficits in 
female breast cancer patients and that healthy older women tend to suffer greater functional 
deterioration with aging and the development of chronic disease compared to men. Thus, we believe 
that women breast cancer patients would have more necessity for alternative exercise interventions, 
such as NMES. We recognize that, if our studies are successful, our work will have to be duplicated in 
other cancer populations, including male volunteers. For these proof-of-principle studies, however, we 
felt that it was prudent to limit our investigation.  
Inclusion of Minorities 
     Every effort will be made to recruit minorities for the proposed studies. The contribution of minorities 
to the total population of Vermont is 3.2%, with a similar minority profile in Chittenden County (3.6%), 
where the University of Vermont (UVM) is located.  
Inclusion of Children:  
The proposed studies will not include children. The rationale for this decision is based on the fact that 
breast cancer is confined to the adult population. There may be instances where the NMES exercise 
intervention being tested in the proposed studies may be useful in children with cancer. However, the 
Belmont Report (Part C, §3) stipulates that research that does not contain a therapeutic component, or 
by extrapolation to the proposed studies, where the utility of the therapeutic component is in question, 
those less burdened populations should be called upon first to accept the risks of research. Accordingly, 
this would mean that adults be studied before children. If our studies are successful, future work could 
determine whether this training modality would be useful in childhood cancers. 
Recruitment:   
Patients will be recruited from the Multi-disciplinary Breast Cancer Clinic of the Division of 
Hematology/Oncology, as well as local, private practices. 
 
Consent Procedures:   
Someone with a treatment relationship will introduce the study to potential volunteers. If the patient 
expresses interest in the study and would like more information about the study, the research coordinator 
or PI will contact the volunteer, briefly explain the study and will provide a copy of the informed consent. 
The PI and/or the research coordinator will answer any questions by phone or in person. Moreover, the 
PI or the research coordinator will discuss the protocol with the volunteer at length and answers any 
remaining questions.