Our study revealed that the most significant risk factor for objective LE after ALND was irradiation of the supraclavicular field and not chemotherapy alone, breast/chest wall irradiation alone, or BMI alone. Radiation can lead to increased scarring and LE, and post-radiation scarring can be more pronounced in the postoperative axilla. Several studies have reported that irradiation of supraclavicular fields is a risk factor for LE after ALND [13, 17–19]. Sherry et al. reported that regional irradiation after ALND further increased the incidence of LE [18]. Consistent with this finding, in the current study, we also revealed that breast/chest wall irradiation alone was not associated with a higher risk of LE, but supraclavicular irradiation was found to be a risk factor for LE. This suggests that irradiation of the supraclavicular area increases the risk of LE after ALND. Lymphatic flow from the upper extremities goes to the axillary lymph nodes, which in turn drain to the subclavian lymphatic trunk along the subclavian vein and then to the confluence of the subclavian vein and the internal jugular vein (venous angle). Therefore, the supraclavicular area has abundant lymphatic flow in the upper extremities, and this may have been caused by the disturbance of lymphatic flow secondary to RT of the supraclavicular area, thus leading to LE.
DTX has also been suggested to be a risk factor for LE after ALND. The proposed mechanism by which DTX causes LE is the inflammation of vascular endothelial cells, resulting in abnormal capillary permeability [20, 21]. Furthermore, it has been reported that postoperative transient LE is more likely to occur with taxane regimens than with anthracyclines [22]. However, our study showed that DTX alone was not a significant risk factor for LE after ALND. According to Swaroop et al., DTX is a controversial risk factor for LE because it depends on the timing of diagnosis of LE [15]. Thus, one of the reasons why DTX alone was not a risk factor for LE in our study is that the left-right difference between the affected and healthy sides was measured. Moreover, it has been more than one year since the operation, so at least the effect of temporary oedema caused by DTX could be excluded.
Although our study showed that DTX or PTX alone was not a risk factor for LE, the sequential use of supraclavicular irradiation and taxane-containing chemotherapy may increase the risk of LE after ALND. This may be because the increased vascular permeability caused by the taxane regimen can trigger oedema at the site of decreased lymphatic transport capacity and scarring caused by ALND and irradiation of the supraclavicular area. The risk factors for LE are complex, suggesting that a combination of various factors may increase the risk of LE. However, in the comparison of taxane-containing regimens, there was no statistically significant difference between the sequential use of supraclavicular field irradiation with DTX and the sequential use of supraclavicular field irradiation with PTX. This was attributed to the small sample size of each group in this study.
LE is a serious complication in patients with breast cancer, and its prevention has been an area of interest. Studies have shown that early prevention is effective [23, 24]. Recently, Paramanandam et al. reported that prophylactic wearing of sleeves reduced the risk of LE after ALND [25]. For patients who require postoperative supraclavicular irradiation after ALND, breast cancer is more advanced, and adequate systemic treatment and local treatment, including RT, are considered necessary. Therefore, it is important to consider preventive measures to avoid postoperative LE when performing supraclavicular field irradiation following ALND.
The main limitation of our current study was the selection bias. The choice of postoperative chemotherapy regimen is dependent on each physician, and some physicians have avoided DTX for high-risk patients with LE to avoid LE. However, there was no difference in patient background between the PTX and the DTX groups; therefore, it is unlikely to be a major bias in this study. Moreover, the result that the risk of LE after ALND tended to be higher in the cases of sequential use of supraclavicular field irradiation and taxane-containing chemotherapy than in the cases of ALND alone or sequential use of taxane-containing regimen without supraclavicular irradiation still supports the fact that the risk factors for LE are complex and associated with the above mechanisms. In summary, the risk factors for LE are complex, and there are only a few studies on the risk associated with the sequential use of supraclavicular irradiation and taxane-containing chemotherapy. However, as mentioned above, in the comparison of sequential use of supraclavicular field irradiation and each taxane-containing regimen in this study, there were no statistically significant differences due to the small population size of each group. Thus, further studies are needed to determine whether the risk of LE increases with supraclavicular RT versus DTX with supraclavicular RT. In addition, we did not examine the risk of LE based on whether neoadjuvant or adjuvant administration of taxane-containing chemotherapy was used in this analysis, and this point should be examined in the future.