The study was approved by the Institutional Review Board at University of Pennsylvania. Recruitment will be conducted at the Head and Neck Cancer Clinics in the University of Pennsylvania Health System. The protocol has been developed in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines for interventional trials.24 The SPIRIT Checklist and Figure are given in the Appendix.
Overview of study design
This study is a three-arm, prospective, randomized controlled clinical trial to compare: 1) Usual Care, 2) Usual Care Plus LEF-SCP, and 3) Usual Care Plus LEF-SCP Plus Follow-Up. Outcome measures include: 1) feasibility (barriers to implementation, safety, and satisfaction) of the LEF-SCP [Aim 1]; 2) self-efficacy and adherence to self-care [Aim 2]; and 3) LEF progression, symptom burden, and functional status [Aim 3]. The study assessments will take place at five points in time, enrollment, 3-, 6-, 9-, and 12-months post-enrollment.
Individuals will be recruited into the study if they meet the following criteria: 1) post HNC primary treatment; 2) no evidence of cancer; 3) no more than 6 months after completion of initial lymphedema therapy for head and neck lymphedema; 4) > 18 years of age; 5) ability to understand English in order to complete questionnaires; 6) able to complete the onsite training and home self-care activities for LEF management; and 7) able to provide informed consent.
Individuals will be excluded if they have any of the following medical conditions that would prohibit the safe implementation of self-care of LEF: recurrent or metastatic cancer; any other active cancer; acute infection; congestive heart failure; renal failure; cardiac or pulmonary edema; sensitive carotid sinus; severe carotid blockage; or uncontrolled hypertension.
Recruitment: A minimum of 5 participants will be recruited per month. Our previous studies in a similar patient population have achieved recruitment goals in a timely manner. This was largely due to the research team’s dedication, support from attending physicians, and a concerted effort on the part of investigators to minimize patient burden. The volume of patients at the Head and Neck Cancer Clinics in the University of Pennsylvania Health System is sufficient to complete this trial without additional sites. The recruitment procedures used will be identical to those used successfully in our prior studies, such as screening at Head and Neck Cancer Clinics. All direct patient recruitment activities will be conducted at the Head and Neck Cancer Clinics where private rooms are available to be used for conducting clinical research projects.
Randomization and allocation
Participants will have provided written informed consent, been screened, and completed all study baseline measures prior to study group randomization. Seventy-five participants will be randomized via the use of a computer-generated, permuted block program, developed and executed by the study statistician, to one of the three study groups (Usual Care, Usual Care Plus LEF-SCP, Usual Care Plus LEF-SCP Plus Follow-Up) at a 1:1:1 allocation ratio (n=25 per group).
Due to the nature of the interventions, neither participants nor staff can be blinded to the allocation status of the participants.
Content and delivery of interventions
Usual Care group: After completion of the baseline measures, Usual Care participants will receive usual care only without any additional interventions.
Usual Care Plus LEF-SCP group: After completion of the baseline measures, Usual Care Plus LEF-SCP participants will be scheduled for the LEF-SCP training. The training includes three weekly face-to-face sessions composed of a one-hour motivational interviewing (MI) session plus a 1-hour LEF self-care training session. After completion of the LEF-SCP training, participants will be given the LEF self-care educational manual. Participants with internet access will be provided a safe website link to watch the self-care videos. Participants without internet access will be given the DVDs and a DVD player for watching the videos. Participants will be asked to review the manual and videos monthly or more frequently as needed.
Usual Care Plus LEF-SCP Plus Follow-Up group: After completion of the baseline measures, participants in the Usual Care Plus LEF-SCP Plus Follow-Up group will follow the same procedures as the Usual Care Plus LEF-SCP group. In addition, however, participants in this group will be scheduled to meet with the study lymphedema therapist for 3-, 6-, and 9-month LEF follow-ups. Please note that these follow-ups will take place after completion of 3-, 6-, and 9-month follow-up data collection. Each LEF follow-up visit with the lymphedema therapist will take approximately one hour. The lymphedema therapist will check participants’ LEF status, adjust the LEF self-care plan if needed, make new recommendations about LEF self-care, and review and address any potential issues and questions participants may have about LEF self-care. The lymphedema therapist will document the suggestions given to each participant.
Patient characteristics: Demographic Form: This form will be used to collect the following participant data: date of birth, gender, race, ethnicity, education, marital and employment status, area of residence, medical history, alcohol use, tobacco use, and dietary habits. HNC Clinical Form: A medical chart review will be conducted to collect data on the diagnosis date of HNC, primary site, stage, type and dates of treatment, and complications. LEF Treatment Form: The form will be used to collect date of diagnosis of lymphedema and/or fibrosis and treatment history.
Feasibility measures: Recruitment Log includes number screened, number recruited, and barriers to recruitment. Implementation Log-MI Session will be used by the study MI instructor to document barriers of implementing MI sessions. Implementation Log-LEF Self-Care Training Session will be used by the study lymphedema therapist to document barriers of implementing LEF self-care training sessions. Common Terminology Criteria for Adverse Events (CTCAE version 5.0) will be used to document any adverse events.25 LEF-SCP Evaluation (Satisfaction) will be completed by participants in the two LEF-SCP study groups after their 12-month post-enrollment assessment has been completed.
Self-efficacy measure: Perceived Medical Condition Self-Management Scale (PMCSMS): An 8-item generic scale that can be adapted to any specific medical condition (e.g., LEF), will be used to assess self-efficacy in self-managing LEF (Cronbach's alpha: 0.84).26-28
Self-care adherence measures: LEF Self-Care Checklist: The form asks participants to complete a checklist of LEF self-care activities they have performed during the past seven days. Participants will complete this checklist at the baseline, 3-, 6-, 9-, and 12-month follow-ups. Monthly Self-Care Survey: Participants will receive an email survey during the last week of each month during the study follow-up. They will be asked to answer four to five brief questions about their adherence to the LEF self-care activities during the past seven days (e.g., Have you conducted daily self-care for your lymphedema and/or fibrosis during the past 7 days? Response: Yes or No).
LEF evaluation: Digital Photographs of the head and neck region will be obtained at baseline and all follow-up visits. A standardized technique for photography has been established by the team in order to ensure constancy. Head and Neck External Lymphedema-Fibrosis (HN-LEF) Grading Criteria will be used to document participants’ external LEF status. Our previous study supports the scale with content/face validity and good interrater reliability (e.g., kappa = 0.752, p < 0.001).8 Patterson Scale is a validated measure for documenting internal edema in the pharynx and larynx. The scale has good intrarater reliability (weighted kappa, 0.84) and moderate interrater reliability (weighted kappa, 0.54).29 This scale will be completed by participants’ primary physicians as part of standard of care for HNC patients.
Symptom burden: Head and Neck Lymphedema and Fibrosis Symptom Inventory: a patient-reported outcome measure developed specifically to assess lymphedema symptoms in HNC patients. Content and face validity of the tool was reported during the development and preliminary testing of the tool. The tool has 58 items (Cronbach’s alpha for five subscales: 0.80 -0.97).30,31 Vanderbilt Head and Neck Symptom Survey Version 2.0 (VHNSS v2.0): a validated measure of HNC treatment-related symptoms, 50 items (Cronbach’s alpha= 0.94).32-34
Functional status: Jaw Range of Motion Scale: a validated and reliable device for measuring jaw range of motion.35,36 Cervical Range of Motion Device: a validated and reliable device for measuring degree of neck movement.37 Goniometry: a validated and reliable instrument for measuring active and passive shoulder range of motion.38,39
Assumptions underlying each of the proposed statistical summaries and comparative analyses will be evaluated. Transformation of continuous data distributions will be completed as necessary to meet those assumptions. Randomly missed responses to items within assessment tools will be handled via protocols specified by the instrument developers. We expect that entire assessments (e.g., 9-months post) will not be missing at random, thus imputation of missing data are not planned. While this study is a preliminary study of efficacy and effect sizes, a maximum alpha level of 0.05 will be used for the statistical tests.
Feasibility of the LEF-SCP: Descriptive statistical and graphical methods will summarize the rates of participation (recruited vs. consented), log data (e.g., sessions completed), completion of assessments throughout the study, adverse events (safety) and satisfaction data (i.e., LEF-SCP program evaluation) within the two groups assigned to LEF-SCP. Qualitative data analysis will be used to summarize the barriers to performing self-care. It is expected that ≥ 80% of participants will complete the study activities, and ≥ 80% will report acceptable levels of satisfaction with the LEF self-care, thereby demonstrating feasibility of the LEF self-care.
Self-Efficacy and Self-Care Adherence: Descriptive statistical and graphical methods will be used to summarize and visually inspect the PMCSMS scores (self-efficacy), the number and types of self-care activities reported on the LEF Self-Care Checklist within the three study groups throughout the study period. Mixed effects generalized linear models that correct the standard errors for repeated assessments and incorporate appropriate distributional link functions (e.g., log-link for skewed distributions) will be used to generate estimates of the effect of the LEF-SCP on self-efficacy and rates of self-care. Within the analyses, bias-corrected estimates of the interaction of group assignment with time of assessment (baseline, 3-, 6-, 9-, and 12-month follow-up) on the outcome measures will provide the key effects interest (i.e., differences among the groups in the longitudinal patterns of self-efficacy and rates of adherence to self-care).
Preliminary Efficacy of the LEF-SCP: As with the previous aim, descriptive statistical and graphical methods will be used to summarize and visually inspect the measures of LEF, symptom burden, and functional status within the three study groups throughout the study period. Mixed effects generalized linear models with the appropriate link function for the nature of the specific outcome variable being analyzed will be used to generate estimates of the effect of the LEF-SCP on the progression of head and neck LEF, symptom burden, and function measures. Bias-corrected estimates of the interaction of group assignment with time of assessment will provide the key effects interest (i.e., differences between the groups in the patterns or slopes of changes in the outcome measures over time).
Sample size justification
The primary purpose of this study is to inform the feasibility and potential efficacy of a tailored LEF self-care program in the population of HNC survivors with LEF. The proposed sample sizes are believed sufficient for gleaning this information. Rather than formal statistical tests of hypotheses, effect sizes generated are the most critical statistical outcome. The expected analysis sample of three groups (25 per group, total N=75) will meet the critical assumptions for estimating central tendency and variability in the key outcome values, as well as for generating estimates of the effects of the LEF-SCP on self-efficacy, self-care adherence, progression of LEF, symptom burden, and functional status. Given the emphasis on effect sizes, there is no plan to adjust for the multiple measures included in this study and any conclusions regarding statistical significance will be based on a two-sided type alpha of 0.05.
Risks and safety monitoring
Although this is an interventional study, foreseeable risks from study participation are believed to be minimal. The key components of the LEF-SCP was developed based on the current standard of care of LEF as well as the IMB model of health behavioral change. All these key components have been used in individuals with other chronic conditions. No physical risks (e.g., worsening LEF) from practicing these components have been reported in the known current literature review. However, if study staff identify LEF-associated issues (e.g., infection, sudden increase in swelling) requiring intervention, the PI, study physician, and study lymphedema therapist will be notified immediately. Patients will be referred to their treating physicians and lymphedema therapist for adequately managing their LEF in a timely manner.
Reporting of Unanticipated Problems
The PI, study physician, and study lymphedema therapist will review any adverse events and other unanticipated problems. The PI will report any adverse events and other unanticipated problems the University of Pennsylvania IRB and the American Cancer Society.
Withdrawal and Discontinuation
Participants will be withdrawn from the study if they develop recurrent or metastatic cancer and any other active cancer.
All participants will be assigned a study ID number. Numbers will be assigned by trained study staff. This information will be maintained in a patient tracking database that is not stored on the hard drive, accessible only to the study team members through a password protected computer and link to the server at the study site, which is accessible only the study team.