Dosimetric analysis of the brachial plexus among patients with breast cancer treated with post-mastectomy radiotherapy to the ipsilateral supraclavicular area: report of 3 cases of radiation-induced brachial plexus neuropathy

Clinical trials have confirmed that adjuvant postmastectomy radiotherapy (PMRT) can improve the locoregional control rate (LCR) and survival rate of patients with locally advanced breast cancer, especially with axillary lymph node metastasis [1]–[3]. The incidence of recurrence in ipsilateral supraclavicular or infraclavicular fossa without PMRT is 4%-8%, when patients had locoregional recurrence, supraclavicular or infraclavicular fossa was involved in 23%-43% of failures [4]–[7]. Therefore, the guidelines of the National Comprehensive Cancer Network (NCCN) and the German Society of Radiation Oncology (DEGRO) recommend irradiation to chest wall (breast) and the ipsilateral supraclavicular (ISCL) area for patients with locally advanced breast cancer [8],[9]. Because of the curative intent of breast cancer surgery, attention should be given to late-stage injury after PMRT. It has been reported 14%-20% breast cancer patients developed radiation-induced brachial plexus neuropathy (RIBPN) after radiotherapy in recent years [10],[11].

The brachial plexus (BP) is formed by the last 4 cervical nerves (C5-C8) and the 1st thoracic nerve (T1). RIBPN symptoms include upper extremity numbness, pain, weakness, and motor disturbance. RIBPN is slowly progressive and often leads to permanent disability and seriously affects the quality of life.

The risk of RIBPN is interested in head and neck cancer treated with high-dose radiation therapy and lung cancer treated with stereotactic body radiotherapy [12],[13]. However, because the conventional fractionated irradiation method is more commonly used in PMRT, BP injury should be different from that occurring with stereotactic body radiation therapy. At present, the BP is not always regarded as an organ-at-risk (OAR) in the optimization and restriction of plans designed for the radiotherapy of breast cancer.

Thus, the purpose of this study was to perform a retrospective analysis of the radiation dose to the BP in 3DCRT plans with PMRT to the ISCL area and chest wall. We further investigated the dosimetric features of the BP in radiotherapy, and the potential correlation with physical features. Lastly, we reported 3 patients with RIBPN after PMRT.

Our analyses of the 3DCRT plans of 31 patients who received PMRT to the ISCL area and CW showed that the dose to the BP was related to irradiation to the ISCL area. This finding is consistent with that of Stanic et al. [18]. There have been few studies on the occurrence of RIBPN symptoms, including worsening chronic pain and decreased sensory and motor function, among the patients with breast cancer, head and neck cancer, and lung cancer after irradiation to the BP [10]–[13],[19]. Importantly, at present RIBPN is an incurable complication.

There is a significant difference in the incidence of RIBPN in the literature. RIBPN incidence is in accordance with the irradiation technique, and ranges from 66% RIBPN with 60 Gy in 5 Gy fractions in the 1960s to less than 1% with 50 Gy in 2.0 Gy fractions today [19]. In present study, the incidence of RIBPN was 0.48%. However, a study which 20% patients developed RIBPN when irradiation to the supraclavicular lymph nodes and chest wall (breast) using 3DCRT technique with 50 Gy in 2.0 Gy fractions [11]. Based on the radiation technique in modern era, the combined treatment-related factors (surgery in the case of haematoma or chronic infection and extended axillary lymph node dissection, et al.) and the patient-related factors (young or advanced age, obesity, hypersensitive patients, or smoking, et al.) may affect the risk, severity, and nature of RIBPN [20]. The follow-up time for different study may also affect the incidence of RIBPN.

It has been reported that the incidence of RIBPN is primarily related to the total dose and fractionated dose to the BP [21]–[23]. Moreover, Killer et al. reported the incidence of RIBPN was positively correlated with the dose to the BP [24]. These findings may be related to the fact that the BP is a serial organ. Therefore, Emami et al. [25] have suggested that the dose tolerance for a 5% risk of developing RIBPN at 5 years is 62, 61 and 60 Gy, and for a 50% risk at 5 years the dose tolerances are 77, 76 and 75 Gy for one-third, two-thirds and the whole organ respectively. Lundstedt et al. reported that the incidence of RIBPN is 20% after conventional fractionation radiotherapy when the prescribed dose to ISCL is 50 Gy [11].

Though the prescribed dose in our patients was 50 Gy, the BP Dmax was higher than 110% of the prescribed dose in some cases. Moreover, for patients with lymph node metastases in the ISCL area, the local dose with boost could be up to 60–70 Gy, which may lead to an increased incidence of RIBPN [26]. For these reasons, we suggest that the BP should be considered as one of the OAR when the ISCL area is planned to be irradiated. But we can not come up with a recommendation of the appropriate dose constraints to brachial plexus due to limited number of patients. The Danish Breast Cancer Cooperative Group recommend the maximum dose to BP should not exceed 54 Gy [27]. In present study, the Dmax to BP in Group 1 and Group 2 are more than 54 Gy. A French study suggested that the Dmax to BP should not exceed 60 Gy, even if possible, 50 Gy [28]. Conventionally, ISCL fields are matched on to tangential breast fields using various techniques [29], the difficulties in matching treatment fields to achieve homogenous dose distribution may results in overdose to BP. Therefore, it is very difficult to achieve a dose of less than 50 Gy of BP. Helical tomotherapy and integrated IMRT treatment plans improved the dose distribution of the supraclavicular region and showed better dose conformity and uniformity of the integrated target volume of the chest wall and supraclavicular region without the requirement of field matching [26],[30]. Thus, the new irradiation techniques with brachial plexus-sparing may be beneficial to the protection of the brachial plexus.

There have few studies on the relationship between the dose to the BP and morbidity, disease severity, and chemotherapy [24]. In addition, unconventional fractionated irradiation is becoming more widely used, which may potentially lead to an increased incidence of RIBPN [10],[21],[31]. Thus, it is necessary to establish risk models for RIBPN based on DVH or normal tissue complication probability models in further research.

In present study, the Dmax to BP was not associated with RIBPN, but patients with a higher number of RLNs were the independent factor associated with RIBPN development. Thus, the dose to the BP should be decreased as much as possible when the dose to the planned target volume is satisfied in patients with a higher number of removed lymph nodes. In addition, lymphedema after axillary dissection can cause brachial plexus neuropathy in breast cancer patients. It was about 13% patients developed brachial plexus neuropathy after axillary dissection without regional radiotherapy. Radiotherapy to the supraclavicular lymph nodes after axillary dissection increases the incidence of brachial plexus neuropathy. When adjusted for lymphedema the contribution from radiotherapy is no longer formally statistically significant indicating that there is also an indirect effect mediated by the lymphedema [11].

Olson et al. [32] and Lundstedt et al. [11] have reported that the incidence of RIBPN was higher in young patients. This is consistent with our finding of a negative correlation between BP Dmax and age. However, it was also reported that there was no correlation between age and the incidence of RIBPN [23]. In addition, our study showed that BP Dmax was negatively correlated with BMI and body weight, which is the same as reported by Klein et al. [33]. These findings indicate that the dose to the BP is relatively higher in slim patients. This, to a certain degree, explains why RIBPN is more likely to occur in slim and young patients. In present study, patients with younger age, shorter height and lower weight had a borderline significant trend with RIBPN development. The further studies with a larger sample size are needed to confirm our study.

Of the 629 patients with irradiation to the ISCL area and chest wall, only 3 (0.48%) developed RIBPN. The development of the RIBPN symptoms in the 3 patients had a relatively long latent period; thus, a diagnosis of RIBPN may be delayed because of mile symptoms in the early stage of the condition. On the other hand, the disease results in progressive and irreversibility deterioration and conservative treatment is ineffective. Surgical treatments including BP neurolysis and revascularization by enveloping the BP using a greater free omental flap have not provided satisfactory results [23]. Induced pluripotent stem cell (IPSC) therapy is a new promising technique that is still in the preclinical testing stage. Because comprehensive management of breast cancer has resulted in greater long-term survival, greater attention should be paid to prevent the occurrence of RIBPN.

There are several limitations to this study that should be considered. First, the study was retrospective, and the sample size was relatively small. In addition, the follow-up duration was relatively short, and the number of reported RIBPN cases was small. Therefore, the results cannot represent the majority of population.

In summary, the incidence of RIBPN was higher in patients with a higher number of RLNs after PMRT. The dose to the BP is primarily from irradiation to the ISCL area, and is higher in slim and young patients. Prevention should be the main focus of managing RIBPN, especially for slim and younger patients. Based on the results of this study, we suggest that the BP should be considered an OAR when designing a radiotherapy plan for the ISCL area.