This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Cancer, is properly cited. The complete bibliographic information, a link to the original publication on https://cancer.jmir.org/, as well as this copyright and license information must be included.
The-Optimal-Lymph-Flow (TOLF) is a patient-centered, web- and mobile-based mHealth system that delivers safe, easy, and feasible digital therapy of lymphatic exercises and limb mobility exercises.
The purpose of this randomized clinical trial (RCT) was to evaluate the effectiveness of the web- and mobile-based TOLF system for managing chronic pain and symptoms related to lymphedema. The primary outcome includes pain reduction, and the secondary outcomes focus on symptom relief, limb volume difference measured by infrared perometer, BMI, and quality of life (QOL) related to pain. We hypothesized that participants in the intervention group would have improved pain and symptom experiences, limb volume difference, BMI, and QOL.
A parallel RCT with a control–experimental, pre- and posttest, and repeated-measures design were used. A total of 120 patients were recruited face-to-face at the point of care during clinical visits. Patients were randomized according to pain in a 1:1 ratio into either the arm precaution (AP) control group to improve limb mobility and arm protection or The-Optimal-Lymph flow (TOLF) intervention group to promote lymph flow and limb mobility. Trial outcomes were evaluated at baseline and at week 12 after the intervention. Descriptive statistics, Fisher exact tests, Wilcoxon rank-sum tests, t test, and generalized linear mixed effects models were performed for data analysis.
At the study endpoint of 12 weeks, significantly fewer patients in the TOLF intervention group compared with the AP control group reported chronic pain (45% [27/60] vs 70% [42/60]; odds ratio [OR] 0.39, 95% CI 0.17-0.90;
The TOLF intervention had significant benefits for breast cancer survivors to manage chronic pain, soreness, general bodily pain, arm/hand swelling, heaviness, and impaired limb mobility. The intervention resulted in a 13% reduction (from 40% [24/60] to 27% [16/60]) in proportions of patients who took pain medications compared with the AP control group, which had a 5% increase (from 40% [24/60] to 45% [27/60]). A 12% reduction (from 27% [16/60] to 15% [9/60]) in proportions of patients with ≥5% limb volume differences was found in the TOLF intervention, while a 5% increase in the AP control group (from 40% [24/60] to 45% [27/60]) was found. In conclusion, the TOLF intervention can be a better choice for breast cancer survivors to reduce chronic pain and limb volume.
Clinicaltrials.gov NCT02462226; https://clinicaltrials.gov/ct2/show/NCT02462226
RR2-10.2196/resprot.5104
Annually, more than 260,000 women are diagnosed with breast cancer, and currently there are more than 3.8 million breast cancer survivors in the United States [
While significantly more breast cancer survivors with a diagnosis of lymphedema experience pain (45.2%), tenderness (52.4%), aching (61.9%), or soreness (31%), a substantial amount of breast cancer survivors without a diagnosis of lymphedema also experience pain (40%), tenderness (47.3%), aching (30%), or soreness (32.7%) [
Pain and lymphedema symptoms are debilitating late complications that impact the breast cancer survivors’ quality of life (QOL) [
While more research is needed to explore the exact etiology of persistent pain and lymphedema symptoms (eg, arm swelling, breast swelling, chest wall swelling, heaviness, firmness, tightness, stiffness, numbness, burning, stabbing, tingling, and limited limb movement), physiologically, the accumulation of lymph fluid in the affected area or limb may create undue pressure on nerves, producing feelings of pain, aching, tenderness, soreness, burning, tingling, stabbing, and numbness as well as inducing sensations of swelling, heaviness, tightness, and firmness [
Breast cancer survivors are known to have a compromised lymphatic system due to breast surgery, dissection of lymph nodes and vessels, and radiation, which leads to ineffective lymphatic drainage, thus accumulation of lymph fluid in the affected area or limb [
Patient education focusing on self-care strategies holds great promise for reducing the risk of lymph fluid accumulation [
Grounded in research-driven self-care behavioral strategies [
The purpose of this randomized clinical trial (RCT) was to evaluate the efficacy of the web- and mobile-based TOLF system, a patient-centered educational and behavioral symptom management program focusing on promoting lymph flow, improving limb mobility, and optimizing BMI, for managing chronic pain and lymphedema symptoms.
The primary objective of this study was to determine the effectiveness of the web- and mobile-based TOLF system for managing chronic pain, aching, soreness, tenderness, and general bodily pain among breast cancer survivors. We hypothesized that more patients who received the TOLF intervention would report a complete reduction and reduced severity of pain, aching, soreness, tenderness, and general bodily pain compared with patients who received the arm precaution (AP) control at week 12 after the intervention.
The secondary objective of the study was to evaluate the effectiveness of the web- and mobile-based TOLF system for managing lymphedema symptoms, limb volume differences, BMI, and QOL related to pain. We hypothesized that patients who received the TOLF intervention would report fewer lymphedema symptoms, minimal limb volume differences, and better BMI and QOL compared with patients who received the AP control.
This study (IRB# i15-00221) was approved by the Institutional Review Board of New York University Langone Medical Center on June 8, 2015.
Chronic pain, including aching, soreness, and tenderness, is defined as persistent or intermittent pain in the ipsilateral upper limb or body at least 3 months after surgical treatment for breast cancer, that is, beyond the expected period of healing [
The study was conducted in a nursing research laboratory located in the breast cancer clinic of New York University Laura and Isaac Perlmutter Cancer Center, a National Cancer Institute–designated cancer center in New York City.
Study participants included (1) patients who received surgical treatment for cancer at least 3 months prior to the study enrollment, because healing usually occurs within 3 months of surgical treatment for cancer [
Exclusion criteria were (1) patients who did not report any pain, including aching, soreness, or tenderness; (2) patients who had a known metastatic disease or other bulk disease in the thoracic or cervical regions; (3) patients who had lymphedema due to cancer recurrence; and (4) patients who had documented advanced cardiac or renal disease.
From June 17, 2015, to December 1, 2016, we screened 283 patients for eligibility and enrolled and randomized 120 patients and followed the participants for 12 weeks after the intervention. Among the 283 patients screened, 163 were excluded for the following reasons: (1) not meeting inclusion criteria (n=145) and (2) declined to participate (n=18). Participants were recruited face to face at the point of care during clinical visits from the New York University Perlmutter Cancer Center.
CONSORT-EHEALTH flowchart for recruitment.
To accomplish the recruitment of 120 participants, we used the successful procedures of recruiting and consenting participants used by the principal investigator and the team in the preliminary studies [
After reading the
The randomization assignment was generated by our senior statistician (GY) using a computer-generated randomization procedure. Participants were randomized based on their report of pain/aching/soreness or tenderness to be allocated with a 1:1 ratio to either the TOLF intervention or the AP control group. The researchers who performed pre- and postintervention measurements were blinded throughout the study to the participants’ assigned arm. Participants did not know which intervention was the intervention of interest and which one was the comparator. Of the 120 patients enrolled, 60 were assigned to the TOLF intervention group and 60 to the AP control group (
The web- and mobile-based TOLF system [
The-Optimal-Lymph-Flow Program: self-care strategies, rationales, and actions.
Strategies and exercises | Rationales | Actions | ||||
|
||||||
|
Muscle tightening deep breathing |
The whole-body lymph fluid has to be drained through the lymphatic ducts above the heart. Muscle tightening–deep breathing stimulates lymphatic ducts and helps lymph fluid drain. Lymph fluid drains when muscles move. Muscle tightening–deep breathing creates the whole-body muscle movements that create muscle milking and pumping action and help to drain lymph fluid. |
At least twice a day in the morning and at night before brushing teeth or as much as the patient wants throughout the day. Air travel: before take-off and after landing. Sedentary lifestyle: At least every 4 hours. |
|||
|
Muscle tightening–pumping |
Muscle tightening–pumping exercises create arm muscle pumping. This helps lymph fluid flow and decreases the fluid build-up in the arms. Muscle tightening–pumping exercises build the arm muscle that helps lymph fluid flow and drain. |
At least twice a day in the morning and at night before brushing teeth or as much as the patient wants throughout the day. Air travel: before take-off and after landing. Sedentary lifestyle: At least every 4 hours. |
|||
|
||||||
|
TOLFa limb mobility exercises: shoulder rolls, clasp and spread, and reach to the sky. Arm precaution limb mobility exercises: shoulder rolls, clasp and spread, reach to the sky, wall climb, and sideway wall stretches. |
Improved limb mobility after surgery facilitates local muscle movements that create muscle milking and pumping to promote local limb lymph fluid flow and drain. Shoulder exercises create arm muscle milking and pumping by moving the main anterior upper arm muscles (biceps brachii, brachialis, coracobrachialis), the posterior muscle of triceps brachii, and deltoid muscle (ie, the anterior deltoid, lateral deltoid, and posterior deltoid). |
One week after surgery if there are no surgical drains or after the surgical drains are removed. At least twice a day until limb functions are returned to normal. Whenever limb mobility is limited throughout the recovery. |
|||
|
||||||
|
Eat nutrition-balanced diet (ie, more vegetables and fruits as well as quality proteins). Maintain portion-appropriate diet (feeling 75% full for each meal). |
Overweight or obesity is an important risk factor for lymph fluid accumulation. Having extra weight makes it difficult for lymph flow and drain. This can lead to extra lymph fluid build-up. There are numerous weight management programs available to assist with weight loss. Although there are a lot of weight reduction programs, each person may respond differently to each program. The core of the weight management is to eat a nutrition-balanced, portion-appropriate diet. It is also important to stay hydrated, exercise, and get adequate sleep. |
Each meal daily It is important to talk to the nutritionist who can help to find a proper weight reduction program. |
|||
|
Stay hydrated |
People may actually be thirsty, not hungry. |
Drink 6-8 glasses of water daily; in the morning, before and during meals, and throughout the day. Avoid drinks with calories (eg, juices). Drink green tea to boost metabolism. |
|||
|
Large muscle exercises |
Daily large muscle exercises (eg, walking, running, swimming, yoga) help to burn more calories. Daily large muscle exercises also promote lymph flow by creating muscle pumps. |
At least 30 minutes 3 times a week or daily |
|||
|
Get enough sleep |
Lack of sleep increases the production of the stress hormone cortisol, creates hunger, and leads to overeating. Getting just 1 more hour of sleep per night reduces belly fat accumulation. |
At least 7-8 hours of sleep per night. |
aTOLF: The-Optimal-Lymph-Flow.
Patients assigned to the TOLF intervention group were granted the access to the web- and mobile-based TOLF platform to learn about the program and therapeutic lymphatic exercises during the first in-person research visit. Patients had the access to the website contents of Lymphedema, Diagnosis of Lymphedema, Lymphatic System, Self-care, Therapeutic Lymphatic Exercises, and Ask Experts. Patients also had the access to the 8 avatar videos with step-by-step instructions to perform lymphatic exercises to promote lymph flow and optimize shoulder and limb mobility. In addition, the patients were introduced to an app, and had the choice to use either the web-based program or the app for practicing lymphatic exercises. However, patients in the TOLF intervention group did not have the access to the section
Patients assigned to the control AP group had access to the web- and mobile-based Arm Precaution program to learn about the program and therapeutic limb mobility exercises to promote limb mobility during the first in-person research visit. The AP program also focused on precautionary lifestyle behaviors, such as avoidance of repetitive limb movement, lifting weighted objects, needle punctures, blood draw, and the use of compression garments for air travel in the affected limb [
It took 30-45 minutes for patients to learn all the sections of the program and about 10 minutes to learn the TOLF lymphatic exercises for the intervention group through 8 avatar videos. It took about 5 minutes to perform a set of TOLF daily exercises each time. Participants in the AP control group had access to 5 limb mobility exercise avatar videos and it took 3 minutes to perform a set of limb mobility exercises each time. We encouraged patients to perform the assigned exercises at least twice a day during the 12-week study period.
Data were collected at baseline prior to the intervention, and at week 12 after the intervention. Data collection at each in-person time point took approximately 30 minutes. Within 1 week of enrollment for the clinical trial, patients had baseline assessment of pain and symptoms, limb volume difference, BMI, and QOL. The follow-up in-person assessment occurred at week 12 after the intervention.
Patients had 2 in-person research visits: (1) prior to the intervention: baseline assessment of pain and symptoms, limb volume difference, BMI, and QOL; and (b) week 12 postintervention assessment of pain and symptoms, limb volume difference, BMI, self-care behaviors, and QOL.
Patients in the intervention and control groups received an email that provided a link to assess pain at weeks 4 and 8 after the intervention. Confidentiality of the patients was protected for the online assessment because patients used their study ID to access the online assessment.
A structured tool was used to gather demographic and medical information and verified through reviewing participants’ medical records [
Primary measure focused on pain that was assessed prior to and at week 12 after the intervention during in-person visits as well as at weeks 4 and 8 postintervention online assessment. Secondary measures included symptoms, limb volume difference (measured using an infrared perometer), BMI, and QOL. Limb volume difference (measured using an infrared perometer) and BMI were measured prior to and at week 12 after the intervention during in-person visits. QOL was assessed prior to and at week 12 after the intervention during in-person visits as well as at weeks 4 and 8 after the online assessment.
Perometry (350S; Juzo) was performed on each arm as it was held horizontally. The perometer maps a 3D graph of the affected and nonaffected extremities using numerous rectilinear light beams, and interfaces with a computer for data analysis and storage. A 3D limb image was generated and limb volume was calculated. This optoelectronic method has an SD of 8.9 mL (arm), <0.5% of limb volume with repeated measuring [
The 6-item Pain Impact Questionnaire (PIQ-6), a reliable and valid 6-question health survey, was used to measure the impact of pain on an individual’s functional health and well-being. The PIQ-6 measures the severity of general bodily pain and its impact on work and leisure activities, as well as on emotional well-being within a variety of diseases and general populations. High PIQ-6
Height was measured to the nearest 0.1 cm with a portable stadiometer (Scale-Tronix 5002 Stand on Scale; Scale-Tronix Company) without shoes [
The Risk Reduction Behavior Checklist, a structured self-report checklist, was used to quantitatively assess patients’ self-report of adherence to the assigned interventions at the study endpoint of 12 weeks after the intervention [
The primary endpoint for the study was a complete pain reduction or reduced pain severity reported by the participants at week 12 after the intervention.
The target sample size was 120 participants to account for a potential attrition of 20%, which has been observed in previous studies on breast cancer survivors [
Data downloading and entry were performed independently by 2 researchers who were not involved in data collection and had no conflicts of interest. Moreover, the data analysis was independently assessed by 2 experienced statisticians (MM and LF) who were not involved in the data collection. Data were analyzed using R version 3.6.2 (R Foundation for Statistical Computing). Descriptive statistics were performed for baseline demographic and clinical characteristics using parametric (eg, independent samples
As planned [
As planned [
To test the secondary hypothesis that patients who received the TOLF intervention would report fewer lymphedema symptoms, minimal limb volume differences, and better BMI and QOL compared with patients who received the AP control intervention, independent sample
There was no case of nonadherence to study protocol. No participants had a missing data >20%. Data were missing from the 6 patients due to attrition. Other participants have intermittent missing data throughout the study due to nonresponse. All missing data were not systematic but missing at random. The primary objective of this RCT required nonparametric tests, precluding the use of Rubin’s rules for multiple imputation and intent-to-treat analysis [
Among the 120 enrolled patients, 114 participants completed the study, including 1 case of screen failure. This patient in the control group was deemed ineligible but completed the study because she was diagnosed with other cancer before the end of the study (0.8% [1/114] screen failure). At week 12 after the intervention, 5 participants in the intervention group and 1 participant in the control group did not complete the study (5% [6/120] attrition rate). There were no statistical differences in demographic and treatment characteristics between patients that completed the study and the 6 patients who did not. No statistical differences were also found between participants in the TOLF intervention and AP control groups in terms of demographic and treatment characteristics except that participants in the TOLF intervention group had higher weight compared with those in the AP control group at baseline prior to the intervention. As a result, the randomization scheme based on the presence of pain, aching, soreness, or tenderness created 2 relatively similar patient profiles (
As shown in
Demographic and clinical characteristics of participants at baseline (N=120).
Characteristics | Total (N=120), mean (SD), range | Arm precaution (n=60) | The-Optimal-Lymph-Flow (n=60) | Statistics ( |
|||||||
Age (years), mean (SD), range | 56.7 (10.6), 54.7-58.6 | 56.8 (11.0), 53.9-59.6 | 56.6 (10.3), 53.9-59.2 | .91 | |||||||
Body weight (lb), mean (SD), range | 163.58 (38.2), 156.6-170.5 | 156.2 (39.0), 146.1-166.2 | 171.1 (36.2), 161.7-180.5 | .03 | |||||||
Number of lymph nodes removed, mean (SD), range | 7.3 (7.7), 5.9-9.0 | 7.4 (8.7), 5.1-9.7 | 7.2 (6.5), 5.5-9.0 | .91 | |||||||
Time since breast cancer diagnosis (years) to study enrollment, mean (SD), range | 2.8 (1.2), 2.6-3.0 | 2.7 (1.2), 2.4-3.0 | 2.9 (1.2), 2.5-3.2 | .54 | |||||||
|
|
|
|
Fisher exact test (5) | .79 | ||||||
|
High school or below | 26 (21.7) | 12 (20.0) | 14 (23.3) |
|
|
|||||
|
Associate’s degree | 6 (5.0) | 3 (5.0) | 3 (5.0) |
|
|
|||||
|
Bachelor’s degree | 47 (39.2) | 23 (38.3) | 24 (40.0) |
|
|
|||||
|
Master’s degree | 29 (24.2) | 17 (28.3) | 12 (20.0) |
|
|
|||||
|
Doctoral degree | 7 (5.8) | 2 (3.3) | 5 (8.3) |
|
|
|||||
|
Professional degree | 5 (4.2) | 3 (5.0) | 2 (3.3) |
|
|
|||||
|
|
|
|
Fisher exact test (4) | .16 | ||||||
|
Married | 61 (50.8) | 26 (43.3) | 35 (58.3) |
|
|
|||||
|
Divorced/separated | 16 (13.3) | 11 (18.3) | 5 (8.3) |
|
|
|||||
|
Widowed | 7 (5.8) | 3 (5.0) | 4 (6.7) |
|
|
|||||
|
Partnered | 9 (7.5) | 3 (5.0) | 6 (10.0) |
|
|
|||||
|
Single or never partnered | 27 (22.5) | 17 (28.3) | 10 (16.7) |
|
|
|||||
|
|
|
|
Fisher exact test (4) | .98 | ||||||
|
Asian | 10 (8.3) | 5 (8.3) | 5 (8.3) |
|
|
|||||
|
African American or Black | 22 (18.3) | 12 (20.0) | 10 (16.7) |
|
|
|||||
|
White | 72 (60.0) | 35 (58.3) | 37 (61.7) |
|
|
|||||
|
Hispanic/Latino | 11 (9.2) | 5 (8.3) | 6 (10.0) |
|
|
|||||
|
More than 1 race | 5 (4.2) | 3 (5.0) | 2 (3.3) |
|
|
|||||
|
|
|
|
.80 | |||||||
|
Unemployed | 41 (34.2) | 19 (32) | 22 (36.7) |
|
|
|||||
|
Employed | 79 (65.8) | 41 (68) | 38 (63.3) |
|
|
|||||
|
|
|
|
.84 | |||||||
|
Yes | 36 (30.0) | 19 (31.7) | 17 (28.3) |
|
|
|||||
|
No | 84 (70.0) | 41 (68.3) | 43 (71.7) |
|
|
|||||
|
|
|
|
|
>.99 | ||||||
|
Yes | 60 (50.0) | 30 (50.0) | 30 (50.0) |
|
|
|||||
|
No | 60 (50.0) | 30 (50.0) | 30 (50.0) |
|
|
|||||
|
Fisher exact test (1) | .32 | |||||||||
|
Yes | 19 (15.8) | 12 (20.0) | 7 (11.7) |
|
|
|||||
|
No | 98 (81.7) | 47 (78.3) | 51 (85.0) |
|
|
|||||
|
|
|
|
.29 | |||||||
|
Yes | 93 (77.5) | 44 (73.3) | 50 (83.3) |
|
|
|||||
|
No | 27 (22.5) | 16 (26.7) | 10 (16.7) |
|
|
|||||
|
|
|
|
.52 | |||||||
|
Yes | 71 (59.2) | 33 (55.0) | 38 (63.3) |
|
|
|||||
|
No | 49 (40.8) | 27 (45.0) | 22 (36.7) |
|
|
|||||
|
>.99 | ||||||||||
|
Yes | 39 (32.5) | 20 (33.3) | 19 (31.7) |
|
|
|||||
|
No | 27 (22.5) | 14 (23.3) | 13 (21.7) |
|
|
|||||
|
Fisher exact test (1) | .71 | |||||||||
|
Yes | 71 (59.2) | 40 (66.7) | 41 (68.3) |
|
|
|||||
|
No | 49 (40.8) | 20 (33.3) | 19 (31.7) |
|
|
|||||
|
>.99 | ||||||||||
|
Yes | 48 (40.0) | 24 (40.0) | 24 (40.0) |
|
|
|||||
|
No | 72 (60.0) | 36 (60.0) | 36 (60.0) |
|
|
|||||
|
.56 | ||||||||||
|
Yes | 43 (35.8) | 27 (45.0) | 16 (26.7) |
|
|
|||||
|
No | 76 (63.3) | 33 (55.0) | 44 (73.3) |
|
|
a
As shown in
As presented in
Proportion of patients that reported chronic pain, soreness, aching, or tenderness, and general bodily pain at baseline prior to the intervention and at study endpoint of week 12 after the intervention.
Outcome variables | Arm precaution (n=60) | The-Optimal-Lymph-Flow (n=60) | Fisher exact test of independencea | |||||||||||
|
No pain, n (%) | Pain, n (%) | No pain, n (%) | Pain, n (%) | Odds ratio (95% CI) | |||||||||
|
|
|
|
|
|
|
||||||||
|
Chronic pain | 8 (13) | 52 (87) | 9 (15) | 51 (85) | 0.87 (0.27-2.77) | >.99 | |||||||
|
Soreness | 5 (8) | 55 (92) | 6 (10) | 54 (90) | 0.82 (0.19-3.44) | >.99 | |||||||
|
Aching | 6 (10) | 53 (88) | 10 (17) | 49 (82) | 0.56 (0.15-1.84) | .42 | |||||||
|
Tenderness | 8 (13) | 52 (87) | 12 (20) | 47 (78) | 0.61 (0.20-1.77) | .34 | |||||||
|
General bodily pain | 3 (5) | 57 (95) | 1 (2) | 59 (98) | 1.04b (0.97-1.11) | .37 | |||||||
|
|
|
|
|
|
|
||||||||
|
Chronic pain | 17 (28) | 42 (70) | 28 (47) | 27 (45) | 0.39 (0.17-0.90) | .02c | |||||||
|
Soreness | 17 (28) | 42 (70) | 24 (40) | 31 (52) | 0.53 (0.22-1.22) | .12 | |||||||
|
Aching | 17 (28) | 42 (70) | 26 (43) | 28 (47) | 0.44 (0.19-1.01) | .05 | |||||||
|
Tenderness | 19 (32) | 40 (67) | 24 (40) | 31 (52) | 0.62 (0.27-1.41) | .25 | |||||||
|
General bodily pain | 11 (18) | 48 (80) | 15 (25) | 40 (67) | 0.89b (0.73-1.09) | .28 |
aDegrees of freedom (
bBecause general bodily pain is a very likely outcome prior to the intervention, we report risk ratio rather than odds ratio for this outcome at both time points. The 95% CI corresponds to the risk ratio, and
cStatistical significance.
Proportions of patients with complete pain reduction between the intervention and control groups (“Yes”= complete pain reduction) using Fisher exact tests.
Complete pain reduction | Arm precaution | The-Optimal-Lymph-Flow | Test of group differences | |||||
|
No, n (%)a | Yes, n (%) | No, n (%) | Yes, n (%) | ORb (95% CI) | NNTc | ||
Chronic pain | 40 (78) | 11 (22) | 23 (50) | 23 (50) | 3.56 (1.39-9.76) | .005d | 3.6 | |
Tenderness | 38 (75) | 13 (25) | 29 (69) | 13 (31) | 1.31 (0.48-3.56) | .65 | 16.7 | |
Soreness | 42 (78) | 11 (22) | 28 (57) | 21 (43) | 2.60 (1.03-6.81) | .03e | 4.8 | |
Aching | 40 (77) | 12 (23) | 26 (60) | 17 (40) | 2.16 (0.82-5.86) | .12 | 5.9 | |
General bodily pain | 48 (86) | 8 (14) | 40 (74) | 14 (26) | 2.09 (0.73-6.36) | .16 | 8.3 |
aPercentage is based on numbers of patients who reported chronic pain, tenderness, soreness, aching, and general bodily pain at baseline. That is, denominator for each symptom is different. For example, for chronic pain for the arm precaution group N is 51. There were 51 patients in the arm precaution group who reported nonzero chronic pain at visit 1.
bOR: odds ratio, a measure of effect size. Recommended interpretation: 1.5=small, 2=medium, 3=large. Degrees of freedom (
cNNT: number needed to treat, that is, the number of patients who would need to participate in the TOLF intervention (instead of the AP control) for 1 additional patient to experience a complete pain reduction.
dSignificant at the
eSignificant at the
At baseline, there were no significant differences in terms of median severity of chronic pain (
Severity of chronic pain, soreness, aching, or tenderness, and general bodily pain as well as quality of life (PIQ-6) at baseline prior to the intervention and study endpoint of week 12 after the intervention.
Outcome variables | Arm precaution (n=60), median (IQR) | The-Optimal-Lymph-Flow (n=60), median (IQR) | Independent samples test for between-group differences | ||||||||
|
|
|
Wilcoxon |
W-score | |||||||
|
|
|
|
|
|
||||||
|
Chronic pain | 2 (1-3) | 1 (1-2) | 0.161 (–0.029 to 0.334) | 2125 | .08 | |||||
|
Soreness | 2 (1-3) | 2 (1-2) | 0.165 (–0.008 to 0.346) | 2133 | .07 | |||||
|
Aching | 2 (1-3) | 2 (1-2) | 0.177 (–0.008 to 0.346) | 2089 | .05 | |||||
|
Tenderness | 2 (1-3) | 2 (1-3) | 0.139 (–0.035 to 0.328) | 2048 | .13 | |||||
|
General bodily pain | 2 (1.75-3) | 2 (2-3) | 0.054 (–0.138 to 0.233) | 1908.5 | .56 | |||||
|
Quality of lifeb by PIQ-6c | 56.1 (9.3) | 54.1 (7.5) | 0.234 (–0.125 to 0.601) | 1.30 (112.9) | .20 | |||||
|
|
|
|
|
|
||||||
|
Chronic pain | 1 (0-2) | 0 (0-1) | 0.206 (0.030 to 0.378) | 2001 | .02d | |||||
|
Soreness | 1 (0-2) | 1 (0-2) | 0.117 (–0.071 to 0.292) | 1837 | .20 | |||||
|
Aching | 1 (0-2) | 1 (0-1.75) | 0.160 (–0.032 to 0.335) | 181.5 | .08 | |||||
|
Tenderness | 1 (0-2) | 1 (0-2) | 0.055 (–0.121 to 0.237) | 1723.5 | .55 | |||||
|
General bodily pain | 1 (1-3) | 1 (0-1.5) | 0.188 (0.016 to 0.355) | 1968 | .04d | |||||
|
Quality of lifeb by PIQ-6 | 50.7 (8.1) | 48.4 (7.9) | 0.290 (–0.088 to 0.669) | 1.53 (108.5) | .13 |
aWilcoxon
bFor quality of life, data in columns 2-6 are presented as mean (SD), mean (SD), Cohen
cPIQ-6: 6-item Pain Impact Questionnaire.
dSignificant at the
Cumulative link mixed effects models were used to predict the ordinal pain outcomes (pain, soreness, aching, tenderness) across the 4 measurement time points and to determine group differences in the changes during the study time. As shown in
Binomial mixed effects models were used to assess group differences in the prevalence of chronic pain, aching, soreness, and tenderness across the study time points. Model results (
A cumulative link mixed effects model was also used to predict severity of general bodily pain across the 4 time points and to determine whether the 2 groups differed in how pain scores vary across the 4 study time points. As
At baseline prior to the intervention, there was no significant difference (
Lymphedema symptom occurrence at baseline and after the intervention.
Lymphedema symptoms | Arm precaution (n=60), n (%) | The-Optimal-Lymph-Flow (n=60), n (%) | |||||
|
|
|
|
||||
|
Baseline | 34 (57) | 30 (50) | .46 | |||
|
Week 12 after the intervention | 28 (47) | 17 (28) | .04b | |||
|
|
|
|
||||
|
Baseline | 23 (38) | 30 (50) | .57 | |||
|
Week 12 after the intervention | 14 (23) | 13 (22) | .83 | |||
|
|
|
|
||||
|
Baseline | 7 (12) | 10 (17) | .36 | |||
|
Week 12 after the intervention | 8 (13) | 8 (13) | >.99 | |||
|
|
|
|
||||
|
Baseline | 19 (32) | 16 (27) | .57 | |||
|
Week 12 after the intervention | 21 (35) | 16 (27) | .55 | |||
|
|
|
|
||||
|
Baseline | 29 (48) | 30 (50) | .49 | |||
|
Week 12 after the intervention | 24 (40) | 22 (37) | .76 | |||
|
|
|
|
||||
|
Baseline | 26 (43) | 20 (33) | .40 | |||
|
Week 12 after the intervention | 26 (43) | 15 (25) | .03b | |||
|
|
|
|
||||
|
Baseline | 14 (23) | 9 (15) | .35 | |||
|
Week 12 after the intervention | 10 (17) | 8 (13) | .60 | |||
|
|
|
|
||||
|
Baseline | 25 (42) | 22 (37) | .61 | |||
|
Week 12 after the intervention | 29 (48) | 18 (30) | .10 | |||
|
|
|
|
||||
|
Baseline | 13 (22) | 9 (15) | .47 | |||
|
Week 12 after the intervention | 14 (23) | 7 (12) | .13 | |||
|
|
|
|
||||
|
Baseline | 7 (12) | 4 (7) | .38 | |||
|
Week 12 after the intervention | 8 (13) | 1 (2) | .03b | |||
|
|
|
|
||||
|
Baseline | 3 (5) | 1 (2) | .62 | |||
|
Week 12 after the intervention | 0 (0) | 0 (0) | N/Ac | |||
|
|
|
|
||||
|
Baseline | 20 (33) | 31 (52) | .01 | |||
|
Week 12 after the intervention | 18 (30) | 19 (32) | .96 | |||
|
|
|
|
||||
|
Baseline | 4 (7) | 12 (20) | .03 | |||
|
Week 12 after the intervention | 3 (5) | 9 (15) | .10 | |||
|
|
|
|
||||
|
Baseline | 13 (22) | 10 (17) | .65 | |||
|
Week 12 after the intervention | 13 (22) | 8 (13) | .19 | |||
|
|
|
|
||||
|
Baseline | 25 (42) | 32 (53) | .40 | |||
|
Week 12 after the intervention | 20 (33) | 23 (38) | .74 | |||
|
|
|
|
||||
|
Baseline | 23 (38) | 31 (52) | .29 | |||
|
Week 12 after the intervention | 21 (35) | 29 (48) | .15 | |||
|
|
|
|
||||
|
Baseline | 35 (58) | 22 (37) | .05 | |||
|
Week 12 after the intervention | 34 (57) | 21 (35) | .02b | |||
|
|
|
|
||||
|
Baseline | 10 (17) | 8 (13) | .76 | |||
|
Week 12 after the intervention | 9 (15) | 3 (5) | .08 | |||
|
|
|
|
||||
|
Baseline | 23 (38) | 22 (37) | .84 | |||
|
Week 12 after the intervention | 28 (47) | 15 (25) | .02b | |||
|
|
|
|
||||
|
Baseline | 9 (15) | 6 (10) | .48 | |||
|
Week 12 after the intervention | 11 (18) | 5 (8) | .15 | |||
|
|
|
|
||||
|
Baseline | 15 (25) | 11 (18) | .53 | |||
|
Week 12 after the intervention | 15 (25) | 7 (12) | .07 | |||
|
|
|
|
||||
|
Baseline | 21 (35) | 14 (23) | .27 | |||
|
Week 12 after the intervention | 17 (28) | 9 (15) | .08 | |||
|
|
|
|
||||
|
Baseline | 26 (43) | 27 (45) | .46 | |||
|
Week 12 after the intervention | 27 (45) | 15 (25) | .03b |
aChi-square tests of independence unless any cell sizes are <10, in which case a Fisher exact test was performed.
bSignificant at
cN/A: not applicable.
Outcomes of lymphedema symptoms, limb volume differences, and BMI at baseline and after the intervention.a
Secondary outcome variables | The-Optimal-Lymph-Flow (n=60) | Arm precaution (n=60) | Statistics | |||
|
||||||
|
Baseline | 9.2 (5.4), 7.8-10.6 | 10.6 (4.9), 9.3-11.8 | .14 | ||
|
Week 12 after the intervention | 6.1 (5.1), 4.6-7.4 | 7.6 (5.2), 6.2-8.9 | .11 | ||
|
||||||
|
Baseline prior to the intervention | 29.2 (6.0), 27.6-30.8 | 27.1 (6.4), 25.4-28.8 | .07 | ||
|
Week 12 after the intervention | 29.3 (6.3), 27.6-31.1 | 27.4 (6.5), 5.7-29.1 | .12 | ||
|
|
|||||
|
Baseline |
|
|
.63 | ||
|
Yes | 16 (27) | 13 (22) |
|
||
|
No | 44 (73) | 47 (78) |
|
||
|
Week 12 after the interventiond |
|
.48 | |||
|
|
Yes | 9 (15) | 16 (27) |
|
|
|
|
No | 51 (85) | 44 (73) |
|
aData are presented as mean (SD), range or n (%).
b
cLimb volume difference percent = (affected limb volume – unaffected limb volume)/unaffected limb volume.
dFisher exact test (
Participants reported no adverse events of performing the TOLF lymphatic exercises and limb mobility exercises. In terms of self-reported adherence to the assigned interventions, 87% (52/60) of participants reported performing the TOLF lymphatic exercises twice a day as prescribed, while 83% (50/60) of participants reported performing limb mobility exercises twice a day as prescribed.
The therapeutic lymphatic and limb mobility exercise intervention is an essential component of the TOLF self-care pain management program [
A recent a single-arm feasibility clinical trial with a pre- and posttest design to assess the effects of the TOLF therapeutic lymphatic exercise intervention demonstrated that a single session of a Kinect-enhanced TOLF intervention immediately reduces pain, swelling, and lymphedema symptoms in breast cancer survivors [
Current pain management relies heavily on pharmacological agents, such as opioids and nonsteroidal anti-inflammatory drugs [
Managing pain and lymphedema symptoms is critical to reduce the risk of lymphedema. Breast cancer survivors who report pain on the affected ipsilateral upper limb or body are nearly twice as likely to develop lymphedema [
The TOLF lymphatic exercises were designed to decrease lymph fluid levels. In a previous study [
The strengths of the RCT are a safe novel digital intervention targeting the lymphatic system for chronic pain, 5% (6/120) attrition, rigorous study design with a larger sample size over 100 patients, and the consecutively identified participants with chronic pain. The use of technologically driven digital therapy not only enhanced the fidelity and transparency of the intervention delivery but also the reproducibility of the intervention, which may enhance the generalizability and dissemination of the intervention. The technologically driven delivery model enhanced the patients’ ability to learn to perform the assigned exercise therapy given that they were able to review the assigned exercise therapy on their own schedule and pace virtually anytime and anywhere. Another strength was the daily 5-minute routine of TOLF lymphatic exercises, which was easy for patients to establish in their own routine.
There were fewer limitations of this RCT. In our study, 87% [52/60] patients reported performing the TOLF lymphatic exercises twice a day as prescribed and 83% [50/60] reported performing AP limb mobility exercises. Lack of real-time monitoring limited the study’s ability to explore dose sensitivity for pain. Future study may use wearable devices to monitor patients’ adherence. Accumulation of lymph fluid in the affected area or limb leads to chronic inflammation resulting in pain for breast cancer survivors [
The results of this RCT showed significant benefits of the TOLF intervention for chronic pain, soreness, general bodily pain, and specific lymphedema symptoms (ie, arm/hand swelling, heaviness, limited movement in shoulder and arm) among breast cancer survivors in comparison with the AP control. The TOLF intervention resulted in a 13% reduction (from 40% [24/60] to 27% [16/60]) in proportions of patients who took pain medications compared with the AP control, which had a 5% increase (from 40% [24/60] to 45% [27/60]). In addition, a 12% reduction (from 27% [16/60] to 15% [9/60]) in proportions of patients with ≥5% limb volume differences was observed in the TOLF group and a 5% increase in proportions of patients in the AP group (from 40% [24/60] to 45% [27/60]). These findings suggest that the TOLF intervention should be a better choice for pain management and limb volume reduction in comparison to the AP control. The TOLF intervention is safe, efficacious, and affordable as a replacement or complement therapy for chronic pain management for millions of breast cancer survivors. The low-cost, detailed description of interventions, and technologically driven delivery model of the TOLF make it relatively easy to implement TOLF in clinical practice or at home.
CONSORT-EHEALTH checklist.
Results of the cumulative link mixed effects models for ordinal pain outcomes. Time is centered at baseline prior to intervention=0.
Results of the binomial mixed effects models with logit link for binary pain outcomes (0=no, 1=yes). Time is centered at baseline prior to intervention=0.
Results for the cumulative link mixed effects model for ordinal general bodily pain (left) and the binomial mixed effects model for prevalence (0=no, 1=yes) of general bodily pain (right). Time is centered at baseline prior to intervention=0.
Results from a linear mixed effects model predicting PIQ-6 (Quality of Life) scores. Time is centered at baseline prior to the intervention=0.
arm precaution
mobile health
odds ratio
Pain Impact Questionnaire
quality of life
randomized clinical trial
The-Optimal-Lymph-Flow
The study, entitled “The-Optimal-Lymph-Flow: An e-Health Approach to Enhancing Management of Chronic Pain and Symptoms Related to Lymphedema among Women Treated for Breast Cancer” was supported by Pfizer Independent Grants for Learning & Change (IGL&C) (grant #13371953) and Judges and Lawyers Breast Cancer Alert (JALBCA) with MF as the principal investigator.
None declared.