In the present study, the effects of ESWT as an adjunctive treatment on advanced stage BCRL when CDT alone for a prolonged period had failed were investigated on a group of 11 Stage IIb and III patients. According to our results, there were significant improvements in circumference and ultrasonographic measurements of affected limbs from the beginning of treatment to end of treatment, a period of 13 weeks.
Without early and adequate treatment, BCRL may progress at a rapid pace. Brunelle et al showed that BCRL could progress from the subclinical stage to the clinical stages in as little as 6.1 months[20]. Fibrotic changes and fat depositions occur in advanced BCRL, causing sclerosis in skin and subcutaneous tissue. In the clinical stages of BCRL, in addition to loss of the function of the affected limb, patients run the risk of skin sores and infections in the affected areas, which could exacerbate their condition further[31–32]. Chronic lymphedema is considered generally incurable[31], and recurring BCRL, which could further worsen its impacts, is not uncommon[33–34]. Above all, continuous treatment may be inevitable throughout the lifetime of survivors with chronic lymphedema; for example, patients with chronic venous insufficiency need regular external compression therapy for the rest of their lives[31].
Currently, complex decongestive therapy (CDT), which includes elements such as manual lymphatic drainage, compression therapy, remedial exercise, and skin care, is the standard therapy for BCRL[13, 35–36]. Studies have found that CDT is effective in treating BCRL, however, the treatment effect varies between individuals, due to many factors such as the severity and duration of lymphedema. Michopoulos et al. found that patients with lymphedema of a year or less who received CDT experienced significantly higher reductions in limb volumes than those with lymphedema for more than a year[37]. Other studies have indicated that CDT alone is not sufficient for the effective reduction of advanced-stage BCRL[20, 23]. In the present study, the mean duration of lymphedema for our patients was approximately 85 months prior to treatment, and 6 months of CDT alone had not shown any visible effect, possibly due to the extended periods of fibrosis and adipose deposition in the edematous tissue.
Currently, ESWT could be viewed as an adjunctive therapy for traditional CDT and several studies have demonstrated the effect of ESWT on BCRL[20, 28]. However, in these studies, most of the patients included had mean lymphedema durations of less than 20 months[27, 29–30, 38–39], with 1 study having an average duration of 32.7 months[40] and another 61.9 months[41]. In our study, all the participants are diagnosed with advanced BCRL (stage IIb and III) for more than 6 months.
In addition, the afore-mentioned studies employed ESWT and CDT as either concurrent therapies from the beginning of intervention or as one versus the other. The present study is the first to examine the effects of ESWT as an adjunct to CDT after prolonged CDT by itself had failed, on patients exclusively with late-stage lymphedema. In other words, the present study presents a particularly high challenge for treatment effectiveness, relatively speaking.
Pre-treatment measurements showed significant differences between the affected arm and unaffected forearm with regards to circumference and thicknesses of skin layer and of the subcutaneous tissue layer, with a no significant difference in the thickness of the muscle layer. The upper arm showed similar findings, with one difference: no significant difference in the subcutaneous tissue layer thicknesses. The above finding may reflect the difference of fibrosis severity between the distal and proximal limb regions; i.e., the degree of fibrosis was different between the forearm and upper arm. There are a few possible reasons for this. The forearm has less capacity than the upper arm for containing excessive fluid and protein; among our participants, the forearms tended to palpably more “tense” and have “harder” skin. Another factor may be gravity, which may have caused fibrotic tissue to deposit in the distal part of limb.
El-Shazly et al. evaluated the effect of concurrent ESWT with CDT on patient “skin thickness” via ultrasound, with one group receiving concurrent treatment 3 times a week for 6 weeks, whereas the control group received only CDT for the same time period[30]. The concurrent treatment group showed a significant 22.51% reduction in skin thickness, whereas the control group showed a change of only 1.28%, which was not significant (p = 0.11). However, El-Shazly’s measurements were in the 2 mm range. In the present study, ultrasound evaluations were made of the skin, subcutaneous, and muscle layers separately (all sub-millimeter measurements), contrasting with El-Shazly’s composite measurements. The present study found significant reductions (all p < 0.05) in the skin and subcutaneous tissue layers of the affected limbs after treatment but not in the unaffected limbs (all p > 0.05). Several studies have demonstrated that ESWT upregulates fibroblastic growth factor (FGF2) and VEGF, which may contribute to neoangiogenesis, neocollagenesis, and lymphangiogenesis[27, 28, 42] all of which could have beneficial effects in lymphedema situations. Such improvements were observed not only in the epidermis and dermis layers, but also in subcutaneous tissue of our patients. The difference in scale between our results and those of El-Shazly’s could be attributed to their study having ESWT at the very beginning of treating BCRL, whereas our subjects only started EWST after 6 months of CDT had no visible effect.
In the present study, the muscle layer thickness showed no significant changes in either the affected or unaffected limbs. However, in both limbs, negative reductions were seen, indicating possible muscle growth, possibly due to localized body recomposition as a result of the CDT, and because fibrotic and adipose tissue deposits generally occur in the skin and subcutaneous layers.
Mahran and Thabet evaluated the differences in arm volume and circumference between one group that received only CDT and another with concurrent ESWT and found that both volume and circumference were significantly more reduced in the concurrent EWST group[29]. El-Shazly also evaluated the differences in upper limb volumes pre- and post-treatment, wherein one group received CDT only and the other with concurrent ESWT. They found significant differences not only between the two groups post-treatment but also within the groups, indicating that concurrent ESWT from the beginning of the treatment period may not have had any significant effect[30]. In the present study, concurrent ESWT was deployed after 6 months of CDT. Significant changes were seen in the limb circumference in both the affected distal and proximal limbs but not the unaffected limbs. As the changes in the skin, subcutaneous, and muscle layers did not sum up to the corresponding limb radius circumference, we hypothesized that the addition of ESWT to CDT resulted in the drainage of some lymphatic liquid from the affected tissues.
The present study had several limitations. First, it was single-center study with a relatively small sample size. In addition, 5 of 20 eligible of patients who are eligible dropped out due to the ongoing COVID-19 pandemic. Further research with more patients and more patient groups may be needed.
Second, we did not evaluate for pain or other such variables, such as using a Visual Analogue Score (VAS) for the former or Range of Motion (ROM) for the latter. Patients with BCRL may suffer from pain, limited ROM of the affected limb, or functional impairment, which cannot be demonstrated by circumference and ultrasound measurements. In addition, there was no baseline measurement of the limbs prior to CDT. Considering the fluctuating character of BCRL, if we had been able to include ultrasound measurement 6 months prior to starting ESWT treatment, the result may have been more convincing.
Another limitation is that there was no standardized location for measurements between participants. We chose the locations, with one in forearm and another in arm, with maximal circumference differences between the affected and unaffected limbs to treat and record. This may have resulted in unintended inconsistencies within our results, but we hypothesize that our method better reflects the changes of the affected limbs after treatment.
Finally, ultrasound is a highly operator-dependent tool. To eliminate the variation of measurement between operators, our measurements were completed by a single experienced physician. As all the measurements of the unaffected limbs showed good consistency without significant changes before and after treatment, we regarded any possible measuring errors as minimal and inconsequential.