DOI: https://doi.org/10.21203/rs.3.rs-1866360/v1
Porpose The aims of this study were to identify (1) the incidence and risk factors for axillary web syndrome (AWS) 4 weeks after axillary lymph node dissection (ALND) for individuals with breast cancer (BC), and (2) whether early-intervention physical therapy (PT) could reduce the recurrence of AWS.
Methods A retrospective review of patients with BC receiving ALND and patients with AWS referred to receive PT twice weekly between January 2019 and December 2020 was performed.
Results A total 173 breast cancer patients receiving ALND were enrolled. The incidence of AWS was 18%, and the time to diagnosis was 26.3 days. There was a predominant difference in age (p=0.004), number of removed lymph nodes (p = 0.044), and whether they were receiving neoadjuvant chemotherapy (p =0.002) between patients with and without AWS. These 3 factors were associated with an increased risk of developing AWS. Initial shoulder flexion and abduction were 132.1˚ and 123.4˚, respectively. After 14.8 PT sessions, shoulder flexion and abduction improved to 172.3˚ and 171.8˚, respectively. Improvement in shoulder ROM was
40.2˚ and 48.4˚ in flexion and abduction, respectively, which was significant (p < 0.001).
Conclusion Younger age, higher number of removed lymph nodes and receiving neoadjuvant chemotherapy were associated with an increased risk of developing AWS. Early intervention with a PT program could effectively restore shoulder function and decrease the incidence of AWS in long-term follow-up.
Axillary web syndrome (AWS) is a common morbidity among breast cancer (BC) patients after surgery[1]. AWS, also known as cording or axillary cording, is a clinical entity affecting the soft tissues of the axilla and arm [2]. The earliest report of AWS, in a retrospective study, found an incidence of 6% in BC patients receiving axillary lymph node dissection (ALND) [3]. In two review articles by Mullen LA [2]and Yeung WM,[1] the incidence of AWS ranged from 5.2%[4] to 72% [5] in patients undergoing ALND, and from 0.9% [4] to 45% [2] in patients undergoing sentinel node biopsy.
The etiology of AWS is not completely understood. Moskovitz’s study showed lymphovenous injury, stasis and hypercoagulability in axillary vessels, resulting in thrombosis of large superficial veins or lymphatics of the arm[3]. Leduc evaluated a series of 15 women with AWS, and found that the cords follow the anatomical course of the antero-radial pedicle of the lateral thoracic lymphatic chain nodes in the arm[6]. Reedijk et al and Rashtak reported that biopsy of the cords showed subcutaneous lymphatic vessels[7, 8]. This evidence points to a lymphatic origin of the cords in AWS, although the exact cause of lymphatic obstruction in these patients is not clear[2].
Among patients with a history of BC, the reported risk factors for development of AWS vary. The higher incidence in patients undergoing ALND compared to SLNB, [4, 9, 10] is more established. Agreement on the effect of age and BMI on AWS occurrence is not unanimous. Fukushima KF[11] and O'Toole J [10] reported that those at a younger age had an increased risk for AWS. But Ryans K reported that the chances of AWS development were greater for those over the age of 60[12].
AWS has been reported to cause morbidity, and to be associated with reduced shoulder range of motion (ROM) and an increased risk of long-term reduced function. [9] Physical therapy (PT) intervention for AWS may prove beneficial in limiting subsequent shoulder dysfunction, but there is no consensus in the PT literature regarding optimal treatment or timing of treatment[13, 14].
Some studies reported that AWS appeared within the first three months after surgery, more frequently within the first 60 days [11, 14]. Ryans K reported that, in a third of BC women, AWS predominately occurred within the first 8 postoperative weeks[12]. Yeung et al., in a systematic review, found that 21 of 37 studies reported AWS occurrence within 8 postoperative weeks[1]. Based on the findings of previous studies, the purposes of this study were to identify (1) the incidence and risk factors for AWS within 4 weeks after ALND for individuals with BC, and (2) whether early intervention with PT could reduce the recurrence of AWS.
At Changhua Christian Hospital, patients with BC who received ALND had regular check-ups by a physiatrist (SF Liao) 4 weeks after surgery. AWS was diagnosed by the same physiatrist, with the criteria of a palpable or visible band over the medial arm [3, 9] and limited affected shoulder motion with elbow extension. Patients with AWS were referred to receive PT twice weekly until the ROM of the shoulder returned to normal and the AWS disappeared. The PT programs included a manual lymph-drainage technique to flexibilize the cords[14], mobilization of the shoulder and scapula, and strengthening and stabilization exercise for the shoulder and scapula. Patients were also instructed in a home exercise program, including wall climbing, free weights, and 0.6 kg weight-lifting training for the affected shoulder.
A retrospective review of patients with AWS after ALND for BC who were diagnosed and referred to the Department of Physical Medicine and Rehabilitation, Changhua Christian Hospital, between January 2019 and December 2020, was performed. For the purpose of this study, patients who had a history of affected side shoulder injury were excluded. The data on BC diagnosis and treatment were derived from the hospital’s cancer registry, which contains data on all cancer patients diagnosed at Changhua Christian Hospital since 2005. The study was approved by, and ethical clearance was obtained from the hospital Institutional Review Board (IRB 220636).
Data on the patient, surgical method, cancer stage, neoadjuvant chemotherapy, and length of PT were obtained. The clinical symptoms of pain, tension and heaviness were evaluated using the visual analog scale (VAS). The VAS provided quantifiable, reliable measurements ranging from 0 to 10, with 0 reflecting no symptoms and 10 indicating the worst symptoms. The affected side passive ROM for shoulder flexion and abduction was assessed in the sitting position, with the elbow fully extended, using a standard goniometric method by the same physical therapist (YH Chou). Special attention was given to maintain full elbow extension during movements to prevent individuals from flexing the elbow, which could potentially take tension off the cords[9].
Descriptive statistics (including mean, range, frequency, and percent) are presented for demographic and clinical/treatment factors of interest. The continuous and categorical variables of the two groups were analyzed by independent T-test and chi-squared test. Factors, and a p value < 0.05 were chosen to determine the final predictive factors for logistic regression analysis. The comparison of shoulder ROM between before and after PT was calculated using the paired-T test. All analyses were performed using SPSS Version 20.0 for Windows (SPSS Inc., Chicago, IL, USA). A p value less than 0.05 was considered statistically significant.
A total of 173 BC patients that had received ALND were enrolled into this analysis. The mean age was 55.7 ± 12.3 years old, BMI was 24.5 ± 4.1 kg/m2, and the number of removed lymph nodes was 9.5 ± 6.6; 36.4% (63/173) of patients received neoadjuvant chemotherapy, and 53.2% (92/173) received Taxotere therapy. (Table 1)
| Variables | All (n = 173) | AWS (n = 31) | No AWS (n = 142) | p |
|---|---|---|---|---|
| Mean (SD) age (years) | 55.7 (12.3) | 50.2 (10.7) | 56.8 (12.3) | 0.004* |
| Mean (SD) body mass index (BMI) kg/m2 | 24.5 (4.1) | 24.3 (5.5) | 24.6 (3.8) | 0.747 |
| Onset time after surgery (days) | 26.3(5.6) | |||
| Type of surgery | 0.198 | |||
| Breast-conserving surgery | 63 (36.4%) | 13 (42%) | 50 (35.2%) | |
| Modified radical mastectomy | 53 (30.6%) | 12 (38.7%) | 41 (28.9%) | |
| Nipple-sparing mastectomy | 57 (32.9%) | 6 (19.4%) | 51 (35.9%) | |
| Breast reconstruction surgery | 50 (28.9%) | 11 (35.5%) | 39 (27.5%) | 0.115 |
| Mean (SD) number of removed lymph nodes | 9.5 (6.6) | 12 (5.8) | 9 (6.6) | 0.018* |
| Neoadjuvant chemotherapy | 63 (36.4%) | 19 (61.3%) | 44 (31%) | 0.002* |
| Taxotere use | 92 (53.2%) | 15 (48.4%) | 77 (54.2%) | 0.559 |
| Stage | 0.789 | |||
| I | 50(28.9%) | 9(29%) | 41(28.9%) | |
| II | 72(41.6%) | 15(48.4%) | 57(40.1%) | |
| III | 35(20.2%) | 5(16.1%) | 30(21.1%) | |
| IV | 16(9.2%) | 2(6.5%) | 14(9.9%) | |
| Tension | 0.5 (1) | |||
| Pain | 0.9 (1.5) | |||
| Heaviness | 0.1 (0.5) | |||
| AWS axillary web syndrome | ||||
| * p < 0.05 | ||||
Thirty-one patients were diagnosed with AWS, and the incidence of AWS was 18%. The mean age of the patients was 50.2 ± 10.7 years old, BMI was 24.3 ± 5.5 kg/m2 and the number of removed lymph nodes was 12 ± 5.8. The time to diagnosis of AWS was 26.3 ± 5.6 days. The mean symptoms of pain, tension, and heaviness, using the VAS, were 0.5 ± 1, 0.9 ± 1.5 and 0.1 ± 0.5. (Table 1) There was a predominant difference in age (p = 0.004), number of removed lymph nodes (p = 0.044) and whether neoadjuvant chemotherapy had been received or not (p = 0.002) between the patients with and without AWS. However, there was no difference in BMI, type of surgery, reconstruction or not, and Taxotere chemotherapy use between these two groups. (Table 1) In a subsequent multivariate analysis (Table 2), younger age (OR = 0.95; 95% CI = 0.91–0.99; p = 0.019), a higher number of removed lymph nodes (OR = 1.09; 95% CI = 1.03–1.16; p = 0.007) and receiving neoadjuvant chemotherapy (OR = 2.96; 95% CI = 1.25–6.98; p = 0.013) were associated with an increased risk of developing AWS. For those receiving neoadjuvant chemotherapy, the odds of developing AWS increased by a factor of 2.96.
| Odds Ratio | Lower 95% CI | Upper 95% CI | p value | |
|---|---|---|---|---|
| Age | 0.950 | 0.910 | 0.991 | 0.019* |
| Number of removed lymph nodes | 1.092 | 1.025 | 1.164 | 0.007* |
| Neoadjuvant chemotherapy | 2.956 | 1.252 | 6.980 | 0.013* |
| * p < 0.05 | ||||
Initial shoulder flexion and abduction were 132.1 ± 37.6˚ and 123.4 ± 35.7˚. After 14.8 ± 14.8 PT sessions, shoulder flexion and abduction improved to 172.3 ± 16.2˚ and 171.8 ± 14.9˚, respectively. Improvement in shoulder ROM was 40.2 ± 33.1˚ and 48.4 ± 32˚ in flexion and abduction, respectively, which was significant (p < 0.001). (Table 3)
| Variable (mean (SD)) | Pre-PT | Post-PT | p value |
|---|---|---|---|
| Flexion | 132.1 (37.6)˚ | 172.3 (16.2) ˚ | p < 0.001 |
| Improvement of flexion | 40.2 (33.1) ˚ | ||
| Abduction | 123.4 (35.7) ˚ | 171.8 (14.9) ˚ | p < 0.001 |
| Improvement of abduction | 48.4 (32) ˚ | ||
| Duration of PT (sessions) | 14.8 (14.8) | ||
| PT physical therapy | |||
The incidence of AWS was 18% in our study, which was lower than in other studies [5, 9, 12]. As Koehler LA et al concluded, 47.2% of BC women developed AWS [15], and Ryans K found that AWS occurred in 30% of BC survivors[12]. Our result was due to the more rigorous definition of AWS in our study -- AWS was defined as not only palpable or visible bands, but also limitations of the affected shoulder ROM. Koehler LA defined participants as having AWS when a palpable or visible cord was present in the upper extremity or trunk during maximal shoulder abduction, but such cords did not have to be associated with restriction of shoulder ROM[9, 15]. Fukushima KF [11] reported an AWS incidence of 28.86%, due to their longer follow-up period and having more patients that received MRM (71% vs 30.6%). However, Wernicke AG reported a rate of AWS in ALND patients of only 5.2% in their retrospective review of early-stage BC patients[4]. In our study, 30% of patients had advanced BC, which might have contributed to an increase in the incidence of AWS beyond Wernicke’s result.
We found that younger age, a higher number of removed lymph nodes, and receiving neoadjuvant chemotherapy were associated with an increased risk of developing AWS. Fukushima KF[11] and O'Toole J [10] also reported that younger patients had an increased risk of developing AWS. Fukushima KF found that the average age of patients with and without AWS was 50.5 and 57.6 years, respectively. Fukushima’s result is similar to our finding[11]. But Ryans K had a different finding -- they reported that the chances of developing AWS were 73% greater for participants over the age of 60[12].
Our result revealed that the mean number of removed lymph nodes was 12 in the AWS group and 9 in the non-AWS group. We concluded that a greater number of removed lymph nodes was associated with the risk of developing AWS, similar to the findings of a review article [2] and O'Toole J[10]. Many articles have reported a higher incidence of AWS in patients undergoing ALND compared to SLNB[2, 4, 5]. However, Huang HC found there was no difference in the number of removed lymph nodes between the AWS and non-AWS groups -- it may be that more lymph nodes were dissected in Huang’s study (17.3/14.7 in the AWS/non-AWS groups) than in our patients[16].
Undergoing neoadjuvant chemotherapy was associated the highest risk of developing AWS in our study, by a factor of 2.96. Ryans K reported that neoadjuvant chemotherapy increased the risk of AWS, and they also found that women with AWS had a 44% greater risk of developing lymphedema during the first postoperative year[12]. It may be that neoadjuvant chemotherapy increased body fluid accumulation, and increased the incidence of AWS. But Fukushima KF [11] found there was no difference in AWS incidence, whether the patients received neoadjuvant chemotherapy or not.
Much research has shown that low BMI is associated with a higher risk of AWS [5, 15, 17]. Individuals with a lower BMI tend to have less body mass, and it has been suggested that it is easier to palpate and identify the cords in these patients. The literature suggests that difficulty palpating over adipose tissue could be a factor that inhibits detection of cords and may lead to underestimation of AWS [2, 9, 12]. BMI was not found to be a risk factor for AWS in our study. This could be because BMI was almost the same in the AWS (24.3 kg/m2) and non-AWS (24.6 kg/m2) groups. Our patients were thinner than those in other studies[9]. In our study, approximately 60% of the women were either normal or underweight. In other studies [9, 14], most participants were obese or overweight, no matter whether the AWS (25 kg/m2) or non-AWS (29 kg/m2) group.
The time between diagnosis of AWS and referral to PT was 26.3 days in our study, because BC patients must visit physiatrist clinics within the first postoperative month in our hospital. This was compatible with the findings of Yeung et al[1] and Ryans K[12]. Shoulder abduction ROM was significantly lower in the AWS group in the early postoperative period, which is consistent with Koehler LA’s result[15]. Patients with AWS could achieve full shoulder ROM and return to regular ADL after 14.8 PT sessions. This means that a 7-week PT program could lead to successful improvement in AWS and shoulder ROM. Our PT protocol consisted of a manual lymph-drainage technique to flexibilize the cords[14], mobilization of the shoulder and scapula to relieve shoulder adhesion, and strengthening exercises to stabilize the affected shoulder to prevent further injury. In our study, there was no AWS occurrence 40 days after surgery. This indicates that early intervention could effectively reduce the long-term incidence of AWS, as reported in Koehler LA[9] and Torres Lacomba M’s [14] studies. Although early intervention could effectively improve shoulder function, we should still encourage BC patients to pay attention to the affected shoulder, because, as Wernicke AG reported, the chronic complication of decreased ROM of the shoulder was found in 80.0% of ALND BC patients at a 10-year follow-up[4].
There were limitations to our study, as described below. 1). This was a retrospective analysis, even though the BC patient’s follow-up protocol is well established. 2). Follow-up should be extended to 2 years after surgery and the incidence of lymphedema in AWS recorded, since many studies have concluded that AWS patients have a greater risk of developing lymphedema[10, 12]. Patients who developed AWS within the first postoperative month were almost 3 times more likely to develop lymphedema[12] .
Approximately 18% of BC survivors will have AWS during the first month after ALND. Younger age, a higher number of removed lymph nodes, and receiving neoadjuvant chemotherapy were associated with an increased risk of developing AWS. Early intervention with a PT program could effectively restore shoulder function and decrease the incidence of AWS in long-term follow-up.
Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by YHC,SFL,DRC and STC. YHC and SFL interpreted data and wrote the manuscript. SFL analyzed data. All authors approved the concept of this study and have read and made critical revision to the drafted manuscript.
Funding The work was unfunded.
Data availability The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of interest The authors have no relevant financial or non-financial interests to disclose.
Consent for publication All authors have read and approved the version of the manuscript
Ethical approval Approval for the study was granted by the Ethics Committee of Changhua Christian Hospital Institutional Review Board (IRB 220636).