Investigation of the effect of Low‐Level Laser Therapy on arm lymphedema in breast cancer patients: A noninvasive treatment for an intractable morbidity

Abstract Purpose This article aims to study the effect of Low‐Level Laser Therapy (LLLT) on arm lymphedema in patients who have breast cancer. Methods and Materials Twenty‐three patients were selected in a nonrandomized phase‐2 clinical trial. After measuring the circumference of the affected and unaffected limbs at 6‐points, the volume of the limbs, the degree of mental symptoms on visual analog scale by the patient upon entering the study, and performing an ultrasound on the patient's axilla to locate the fibrotic areas, a low‐level laser device at a therapeutic dose of 2 J/cm2 was used to treat the patients three times a week for 4 weeks, and after an 8‐week gap, for another similar period. Measurement of circumference and volume of affected and unaffected limbs and mental symptoms were carried out at the end of the 4th week, the beginning of the 12th week, and the end of the 16th week, and the obtained results were compared with those before the treatment. Results We noted that the average reductions in the circumference and volume of the affected limb, as compared with the unaffected limb, were about 16% and 21.7%, respectively, and improvement in the patient's mental symptoms was about 32%. Another notable observation was the great enthusiasm of most patients to continue their treatment, particularly from the second cycle onward. Conclusions LLLT can, at least in association with current standard methods, be used for arm lymphedema to introduce further reductions in pain and volume.

Twenty-three breast cancer patients with previous surgery (mastectomy or breast-conserving surgery) and radiotherapy were selected.
The minimum difference in displaced water volume between the affected and unaffected limbs was 200 mL, or the minimum of the average difference between affected and unaffected limbs' circumference, measured at six different locations of the limbs with a measuring tape was 2 cm or 10% (the difference percentage is calculate by dividing the difference between the volume or circumference of the affected and unaffected limbs by the volume or circumference of the unaffected limb, multiplied by 100). All the patients were briefed about the treatment procedure and consequently submitted their written informed consent and agreed to undergo LLLT for an overall period of 2 months with an 8-week interval in between. As it was deemed unethical to deny treatment to a control group who would come and go to and from the medical center in hopes of being treated, and as arm lymphedema is a persistent and progressive complication that does not go away by itself, it was decided, upon consultation with relevant medical experts, that there should be no control group in this study, and that patients should be compared to themselves (arms compared to each other) as "pre-treatment" and "post-treatment" cases.
The criteria for admission to the study included the following: persistence of lymphedema following mastectomy or breast conservative surgery for at least 3 months, and the existence of either a minimum volume difference of 200 mL or an average difference in arm circumference of 2 cm or 10% between healthy and affected limbs.
Exclusion criteria consisted of metastatic or recurrent disease, established vein thrombosis, history of severe arm trauma, chronic inflammatory disease, congenital lymphedema, recent infection, and drugs that affect body fluid balance, pregnancy, and photophobia.

| Study protocol
All patients considered eligible for the study were, before the study's onset and for exact determination of fibrotic areas, examined by a skillful radiologist through ultrasound. The mentioned areas were marked in ink so that the treatment area could be easily distinguished. The treatment protocol is shown in Figure 1.
Patients were subjected to measurement at Week 0, end of Week 4, the start of Week 12, and end of Week 16, and their limb circumferences measured with measuring tape at 6-points: roots of fingers, the wrist, 5 cm above the wrist, the elbow, 5 cm above and 5 cm below the elbow and the average differences between the afflicted and healthy limbs were recorded. Also, the difference in the limbs' volume was determined and recorded through the water volume displacement method. This was done by the trained, skillful personnel of the Physiotherapy Ward. The patients would undergo treatment three times a week for 4 weeks with a low-level laser device of Spotting Pen type (Heltschel Company), with a radiation dose of 2 J/cm 2 , an output of 100 mWatt, and a wavelength of 658 nanometers. The Food and Drug Administration has not declared this laser therapy device for the treatment of postmastectomy lymphedema, and it has been used off-label. After an 8-week rest period, the treatment was resumed for another 4 weeks, coming up to a total of 24 sessions. To ensure our ability to correctly localize the treated area for the next sessions, sheets of radiology films were prepared in which holes were made with a spacing distance of 2 cm and diameters equal to the laser apparatus therapeutic head. Each  The patients and the therapist used protective goggles during all therapeutic sessions. The area of treatment was determined by the radiologist and then divided into 16−24 points for treatment.

| Patient evaluation
Evaluation of the patients was conducted at the end of the 4th week, the start of the 12th week, and end of the 16th week, through measuring the changes produced in the volume and circumference of the affected limbs relative to the healthy side, as well as the mental symptoms (pain, stiffness, paresthesia, heaviness, and organ infirmity), and then compar- This was a phase-2 clinical trial; therefore, no randomizations were performed. Sample size was calculated using a typical Gehan design.
Considering the minimum efficacy of 20% in patients (p = 0.2) and alpha=10%, using the Gehan design, we would need 11 patients (10.    The basic and demographic information about patients is given in Table 1, and the results obtained during treatment are recorded in Table 2. As seen in these tables, the difference in terms of average volume and circumference between the afflicted and the healthy limbs at the onset of the treatment was statistically significant with a P-Value of less than 0.05. The decrease in volume difference between the afflicted and the healthy limbs was more than 200 mL in 59% of the patients, and the decrease in the circumference difference between the afflicted and the healthy limbs was more than 0.5 cm in 53% of the patients. If we compare the average volume and circumference of the afflicted limb before and after treatment, an average volume reduction of 200 mL, that is, 21.7%, and an average arm circumference reduction of 0.5 cm, that is, about 16%, can be observed at the end of the 16th week compared to the first day of treatment, which is statistically significant with a p Value of less than 0.05. However, if the calculations are based on the volume and circumference reductions relative to those of healthy limbs at the end of the 16th week, then the corresponding results would be 9% and 3.5%, which, based on a p Value greater than 0.05, would not be statistically significant.
A closer look at lower rows in Table 2 shows that changes in subjective symptoms are much more visible, and on average, patients have reported a 32% improvement in these symptoms. Focusing on the mental symptoms individually, suggests that treatment has had a greater effect on pain and stiffness than on paresthesia, heaviness, and limb weakness. Moreover, except for two minor nausea and feeling of weakness, no other complications were reported by the patients.
We can observe in Table 3, that the results of LLLT in patients with fewer removed lymph nodes and lesser degree of lymphedema, is more significant and the reduction in variations recorded for volume and circumference difference between afflicted and healthy limbs is greater. This observation might be due to the existence of high interstitial pressure in severely damaged cases, which does not allow any appreciable reduction in volume and arm circumference despite the reduction in edema and stiffness. However, as we have not used skin tonometry in designing our study, we are unable to support this claim with experimental evidence. The same problem exists in patients with a cancer treatment history extending further into the past, that is, those patients with longer duration of their symptoms, who had probably suffered more severe lymphedema, responded less favorably to the treatment.  showed at least 200 mL volume reduction as compared with 4% of the placebo group. In addition, 52% of the patients in case group showed reduced skin tightness as compared with 24% in the placebo group. The average volume reductions in the treatment and placebo groups were 89.7 and 32.1 mL respectively, and their difference amounted to 57.6 mL. As in our study, total average volume reductions in patients were 200 mL. A study by Mohammad Taher et al. 10 showed that laser therapy led to limb volume reduction in 93% of patients and recovery of handgrip strength. In that study, the average circumference reductions in the affected limbs in the treatment and control groups were 31% and 23%, respectively (compared to healthy limbs), with a difference equal to 8%. In our study, reduction in circumference was 16%. Some reports have stated much higher rates for circumference reduction after laser therapy. For instance, Dirican et al. 11   We found that in patients with either "fewer removed lymph nodes" or "lesser severity of baseline lymphedema," the response is more significant. This might be due to the existence of high interstitial pressure in cases of severe damage, which does not allow any

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
Data can be made available upon request.

TRANSPARENCY STATEMENT
The lead author Fatemeh Jafari affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.