Design and participants
This was an open label, randomized, wait-list controlled study conducted at Vanderbilt University and Southern Illinois University School of Medicine. Patients were randomly assigned to receive usual care or FT, according to a sequence of computer-generated random numbers, with stratification by study site. The study was conducted in accordance with the ethical standards of the Helsinki Declaration and registered at ClinicalTrial.gov number NCT03332160. Institutional Review Board (IRB) and Scientific Review Committee approvals were obtained prior to patient recruitment. Eligible patients had completed cancer treatment for histologically proven HNC, recovered from acute treatment effects, and had no evidence of active disease. Patients had a clinical diagnosis of lymphedema in the head and neck region. They had either undergone lymphedema therapy or were unable to access therapy due to defined barriers such as lack of available clinical services or socioeconomic constraints (e.g., lack of insurance, lack of transportation). Additional inclusion criteria included age ≥ 18 years; and able and willing to participate in all aspects of the study; and to provide informed consent. Exclusion criteria included a documented history of: (1) uncontrolled hyperthyroidism or parathyroidism; (2) carotid sinus hypersensitivity syndrome; (3) symptomatic carotid artery disease, as manifested by a recent transient ischemic attack (within 30 days), ischemic stroke, or amaurosis fugax (monocular visual ischemic symptoms or blindness); (4) symptomatic bradycardia in the absence of a pacemaker; (5) internal jugular venous thrombosis, acute or within 3 months; (6) increased intracranial pressure or other contraindications to internal or external jugular venous compression; (7) acute radiation dermatitis, unhealed surgical scar, unhealed or open wound(s), surgical flap less than 6–8 week post-operative; (9) acute facial infection (e.g., facial or parotid gland abscess); (10) any condition in which increased venous and lymphatic return was undesirable (example: history of pulmonary edema or decompensated congestive heart failure within six (6) weeks of enrollment); (11) pregnancy or trying to become pregnant; and (12) interference with tracheostomy function by garment.
Research team members were trained to conduct and document head and neck physical examinations by authors Ridner and Murphy. Eligible patients were consented, and then measured for garment size selection. No subjects were withdrawn due to poor garment fit. Baseline evaluation included a physical exam, endoscopy, completion of questionnaires, and bloodwork. After baseline evaluation, participants were randomized to either wait-list lymphedema self-management (standard of care) or lymphedema self-management plus the use of the FT twice daily for 8 weeks. Time allotted for use varied based upon size of garment and ranged from 23 to 45 min.
All patients received a self-care kit that included a diary, self-care checklist, and date and times of future study appointments. The intervention group received the FT and was instructed on use, including the timer that would record their actual time on the machine. All patients had follow-up visits at 1, 4, and 8 weeks during which they were assessed for adverse events and completion of study measures. For patients in the intervention group, study participation concluded at week 8. Patients assigned to the wait-list group could opt to continue on study for the purpose of using the FT. If they opted to do so, they (1) were provided with the FT for an 8-week treatment period; (2) given the same education prior to use as intervention group; and, (3) were seen subsequently for safety checks at 1, 4, and 8 weeks post-receipt of the FT.
Data collection and instruments
Patients completed a demographic survey at baseline. Disease and treatment data were extracted from medical records.
Safety and feasibility
Safety was evaluated using CTCAE V4.0 . Severe or unexpected adverse events were reportable to the IRB. All patients completed a weekly self-care checklist. The date and time of use were recorded by the device. Those data were exported and analyzed for determining the frequency and duration (minutes) of use per day for patients assigned to the intervention group. A daily diary was completed to document treatment barriers. A six-item survey regarding perceived lymphedema control, management, and health was completed by intervention participants at the baseline, and end of study.
A head and neck physical exam was conducted by trained study personnel. External lymphedema and fibrosis were ascertained by touch and visual inspection. External grading was documented using the Head and Neck Lymphedema and Fibrosis Assessment criteria . Using this tool, skin and soft tissue changes were typed as follows: A—involving skin only, B—reducible soft tissue swelling, C—firm, non-reducible swelling, and D—fibrosis without swelling. Types B, C, and D are then graded as mild, moderate, or severe. The site of soft tissue abnormalities was documented in a table format that includes left and right periorbital region, left and right cheeks, left and right neck, left and right supraclavicular region, and the submental area.
Endoscopic exams were performed by a trained, blinded Otolaryngology nurse practitioner. Internal lymphedema was scored using the Modified Patterson Scale . A grade of normal, mild, moderate, or severe was documented for each site or space.
Digital photographs of the head and neck, each profile and facing forward, were taken and overlaid with a 30 segment grid. Each segment was rated yes/no by a blinded single rater for swelling. A composite score of percentage of grids with swelling was used as an indicator of swelling extent.
Patient reported outcomes
Patients completed symptom assessment and quality of life measures at baseline, 4, and 8 weeks. The Lymphedema Symptom Intensity and Distress Survey-Head and Neck (LSIDS-HN) is a 48-item tool that captured symptom intensity and distress, both independently rated on a scale of 1 (slight) to 5 (severe), yielding a total potential symptom burden score of 10 [3, 17]. The Vanderbilt Head and Neck Symptom Survey plus General Symptom Survey version 2.0 (VHNSS v2.0 plus GSS), a 61-item tool, was used to assess the prevalence and severity of HNC treatment-related symptoms and their functional impact . A 5-item Linear Analog Self-Assessment was used to evaluate quality of life (QOL) .
Cervical range of motion (CROM) were taken using the cervical and shoulder range of motion instrument . Jaw range of motion (ROM) was documented using the TheraBite Jaw ROM Scale . Trismus grading criteria from the CTCAE v4.0 was recorded . Patients completed the Neck Disability Index (NDI) to assess components of daily life that may be affected by neck pain and dysfunction , and the self-report Voice Handicap Index (VHI) garnered data regarding voice disorders .
Blood samples were obtained at baseline and at the 8-week visit for the following inflammatory markers: IFNg, TNF-α, TGF-β1, IL-1b, and IL-6.
Descriptive statistics were used to summarize the demographic, clinical history, and outcome variables in the study. Due to skewness of many of the data distributions, median (IQR) was used for describing the continuous variables. Characteristics of the patients assigned to the separate study arms were compared using Mann-Whitney and Chi-Square tests. Given the preliminary nature of this work, small sample, and considerable variability among the patient scores at baseline, initially the change in the score for each outcome measure was calculated for each patient. Differences between the groups from baseline to the end of the 8-week study period were then conducted using generalized linear regressions that included the patient’s respective baseline values for the outcome variable being analyzed. Inclusion of the baseline values allowed us to control for potential differences between the groups at initial time of assessment and focus on differences between the groups in the amount of change from baseline. An alpha of 0.05 was used for evaluation of statistical significance, and no corrections for multiple tests were used in this preliminary study. Feasibility, adherence, and safety of the FT were the primary outcomes, with efficacy included to generate initial estimates of effect for larger future trials. The adjusted beta coefficient for the study group effect generated by each regression was transformed to the Cohen’s d effect statistic for ease of interpretation of the study effects on patient outcomes.