Abstract
Purpose
The present study is aiming to correlate different radiotherapy techniques, fractionations, and doses received by each axillary LN level and axillary vessels with the development of breast cancer-related lymphedema (BCRL).
Methods and Materials
We retrospectively studied 181 female breast cancer patients who were diagnosed and treated by radiation therapy during the period from January 2012 to December 2017. The radiotherapy treatment plans were recalled from the archives. The axillary LN levels I, II, III, supraclavicular LN were contoured as well as axillary vessels. New dose volume histograms were generated to correlate between the radiotherapy dose t and the development of BCRL.
Results
The study included 162 patients treated with a 3D radiotherapy technique and 19 treated with a 2D radiotherapy technique; 124 patients underwent MRM, while 57 patients underwent BCS; 117 patients were treated with a hypofractionated technique, while 64 patients were treated with a conventional radiotherapy technique. The cumulative incidence of BCRL after radiotherapy was 20.4%. There was a statistically significant relationship between the 2D radiotherapy technique compared with 3DCRT and development of lymphedema (55 vs. 16.6, respectively; p < 0.001). Patients who were treated with conventional radiotherapy had significantly higher rates of lymphedema (42.2%) compared with hypofractionated radiotherapy (8.5%) (p < 0.001). There was a non-significant relationship between mean radiotherapy dose to axillary levels or axillary vessels and development of lymphedema.
Conclusion
Breast cancer radiotherapy with the 2D technique and conventional fractionation protocol might increase the risk of BCRL. No correlation was observed between radiotherapy dose to each axillary LN level, axillary vessels and BCRL.
Keywords: Radiotherapy, Breast cancer, Lymphedema
Introduction
Adjuvant radiotherapy is a crucial pillar in the management of breast cancer patients. It has been proved to improve not only the local control but also the overall survival [1]. However, radiotherapy can result in some long-term toxicities like cardiotoxicity [2], radiation pneumonitis [3], skin toxicity [4], secondary malignancy [5], and breast cancer-related lymphedema (BCRL) [6]. In this regard, BCRL has negative effects on the patients including psychological and physical impairments compared to patients without breast and arm edema [7].
The median overall incidence of BCRL is about 21% of breast cancer cases, while the incidence varies from 5% and up to 50% according to the contribution of many risk factors such as type of nodal surgery either axillary dissection or sentinel lymph node biopsy, body mass index (BMI), cellulitis, and radiotherapy techniques especially with regional nodal irradiation (RNI) [8, 9].
In this context, two large, randomized trials for early-stage high-risk feature breast cancer (EORTC 22922 and the MA20) have shown improvement in disease-free survival with the addition of RNI to whole breast irradiation, also showed that positive effect of RNI is not without drawbacks [10, 11]. These trials showed that BCRL is significantly increased when regional nodes either supraclavicular alone or with whole axillary nodes were irradiated. Nevertheless, a recent meta-analysis published by Shaitelman et al. [12] showed that RNI increased the risk of development of BCRL, especially when it was combined with ALND, while the effect was smaller when it was combined with sentinel lymph node dissection.
Furthermore, radiotherapy to the breast can be either delivered with conventional fractionation or hypofractionation that proved to give similar efficacy in the local control as well as the risk of BCRL in large 3 randomized trials, START A, START B, and the Canadian study [13, 14]. Unfortunately, a small subset of patients in those trials received RNI; therefore, the effect of fractionation size on BCRL is still questionable. Moreover, standard radiotherapy fields and high tangential fields to chest wall or breast alone can deliver around 80 and 55% of the prescription dose to level I and II axilla, respectively [12]. Certainly, higher doses to all axillary levels will be received with treating breast or chest wall with RNI. To this end, correlation of the radiotherapy dose received by each axillary level and the development of BCRL is still an area of study.
In this study, the primary end point is to assess the relation between different radiotherapy techniques and fractionations and the development of BCRL. The secondary end point is to study the correlation between the radiotherapy dose received by each level of the axilla and axillary vessels and the development of lymphedema.
Materials and Methods
We retrospectively studied 181 female breast cancer patients presented to our department during the period between January 2012 and December 2017; the inclusion criteria were female breast cancer patients who received radiotherapy to the breast/chest wall with RNI and availability of their treatment plans. Patients with known lymphedema or any lymphatic disease before diagnosis, patients with bilateral or metastatic breast cancer or patients who did not complete the radiotherapy course were excluded from the study. An informed consent was signed by all participants who fulfilled the inclusion criteria.
Patients' data including the demographics and baseline characteristics, risk factors of lymphedema development, pathological details, and treatment received, were collected from the patients' records.
Lymphedema measurements were calculated by the difference in arm circumference in comparison to the contralateral healthy side in 5 fixed points from wrist joints at 0, 10, 20, 30, 40 cm to define the incidence of lymphedema. These measurements were done at baseline before start of radiotherapy and any patient with difference in arm circumference by more than 5% was excluded from the study then at 3 months and 6 months later and every year from the baseline measurement. Lymphedema was defined as an increase in the mean arm circumference >10% at any point of the 5 points compared to the contralateral side.
Radiotherapy treatment plans for all patients were recalled from the backup archives, then axillary level (I, II, III) and supraclavicular groups were contoured according the RTOG contouring atlas [15]. Transverse axillary vessels were contoured as well to study the relation between their doses and the development of BCRL.
New dose volume histograms (DVHs) were generated for the patients treated with the 3D technique, and the minimum, mean, and maximum doses were calculated. All radiotherapy dosimetrics including the radiotherapy technique (2D or 3D) (all patients were treated with the 3-field technique), mean dose, energy, fractionation (conventional or hypofractionation), the dose received by all axillary levels (I, II, III), supraclavicular and axillary vessels were correlated with the lymphedema development.
Statistical Analysis
Descriptive analysis was done to demonstrate the demographic and baseline characteristics. Univariant analysis was done to correlate between the radiotherapy dose and fractionation and the development of BCRL. Logistic regression multivariate analysis was used to identify the most important radiotherapy factors which might predict the rates of BCRL. For all analyses, two-sided p values of <0.05 were considered statistically significant.
Results
A total of 181 patients fulfilled the inclusion criteria, and the median age was 51 years. Seventy-nine patients (43.6%) had right-side disease, while 102 patients (56.4%) had left-side breast cancer. Most of our patients had BMI 25 or more (151 patients [83.4%] had BMI 25 or more). Slightly more premenopausal women (97 [53.6%]) were included in our cohort. More patients underwent modified radical mastectomy than breast-conserving surgery (124 [68.5%] vs. 57 [31.5%] patients). Axillary LN dissection was the most common type of axillary surgery, and all of them had dissection of level I and II; 174 (96.1%) patients had ALND with a mean number of 13 LN dissected, and a mean number of 5 of them were positive nodes (N0 5%, N1 44.2%, N2 39.8%, and N3 11%). Stages II and III represent 40.9 and 54.7% of patients, respectively. Note that most of the patients had locally advanced tumors. Baseline demographic and pathological characteristics of the study population are presented in Table 1.
Table 1.
Baseline demographic characteristics of the study population
| Disease side | Right side | 79 (43.6%) |
| Left side | 102 (56.4%) | |
|
| ||
| Family history | Yes | 17 (9.4%) |
| No | 164 (90.6%) | |
|
| ||
| Menopausal status | Premenopausal | 97 (53.6%) |
| Perimenopausal | 32 (17.7%) | |
| Postmenopausal | 52 (28.7%) | |
|
| ||
| Body mass index | Less than 25 | 22 (12.2%) |
| 25 or more | 151 (83.4%) | |
| Not reported | 8 (4.4%) | |
|
| ||
| History of diabetes | Yes | 35 (19.3%) |
| No | 146 (80.7%) | |
|
| ||
| History of hypertension | Yes | 49 (27.1%) |
| No | 132 (72.9%) | |
|
| ||
| Type or surgery | MRM | 124 (68.5%) |
| BCS | 57 (31.5%) | |
|
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| Type of LN surgery | ALND | 174 (96.1%) |
| SLN | 7 (3.9%) | |
|
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| T stage | T1 | 87 (48.1%) |
| T2 | 84 (46.4%) | |
| T3 | 10 (5.5%) | |
|
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| Lymph node status | Mean LN dissected | 13 |
| Mean LN positive | 5 | |
| Mean LN negative | 8 | |
|
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| Final stage | Stage I | 8 (4.4%) |
| Stage II | 74 (40.9%) | |
| Stage III | 99 (54.7%) | |
|
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| ER status | Positive | 146 (80.7%) |
| Negative | 35 (19.3%) | |
|
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| Her2 status | Positive | 42 (23.2%) |
| Negative | 139 (76.8%) | |
|
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| Tumor grade | Grade 1 | 4 (2.2%) |
| Grade 2 | 109 (60.2%) | |
| Grade 3 | 62 (34.3%) | |
| Not reported | 6 (3.3%) | |
Regarding the systemic treatment received, most of the patients received adjuvant chemotherapy (154 [85.1%]), while only 14 (7.7%) of the patients received neoadjuvant chemotherapy. Anthracycline plus taxanes protocol was used more (96 [53.1%] patients) compared to anthracycline alone (77 [42.5%] patients). Adjuvant hormonal treatment was used in all patients with hormone receptor-positive breast cancer (63 patients [34.8%] and 83 patients [45.9%] received tamoxifen and AI, respectively).
3DCRT was the main type of radiotherapy received by our patients, with 162 (89.5%) compared to only 19 (10.5%) patients who received 2D radiotherapy. Hypofractionation treatment in the form of 40 Gy/15 fractions was administered to 117 (64.6%) patients, while 64 (35.4%) patients received conventional fractionation radiotherapy.
Effect of Different Risk Factors on the Development of Lymphedema
The median follow-up was 44 and 46.5 months for patients treated with hypofractionation and conventional fractionation, respectively. Lymphedema was identified in 37 (20.4%) of patients in our cohort. There was no statistically significant difference between the type of surgery and the development of BCRL. Twenty-two of 124 (17.7%) patients who had modified radical mastectomy and 15/57 (26.3%) patients who had breast-conserving surgery developed BCRL (p = 0.23). Patients with BMI less than 25 developed less lymphedema compared to those with BMI 25 or more (3/22 [13.6%] and 34/151 [22.5%] of patients, respectively). However, this difference was not statistically significant (p = 0.43). Regarding the type of axillary surgery, 37/174 (21.3%) patients who developed lymphedema had axillary lymph node dissection, while no patients in the SLN group had lymphedema (Table 2).
Table 2.
Effect of different risk factors and development of lymphedema
| Factor | Lymphedema | p value | |
|---|---|---|---|
|
| |||
| Type of surgery | MRM | 22/124 (17.7%) | 0.23 |
| BCS | 15/57 (26.3%) | ||
|
| |||
| Type of axillary surgery | ALND | 37/174 (21.3%) | NS |
| SLND | 0/7 (0%) | ||
|
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| High nodal positivity | 0–3 LNs | 17/89 (19.1%) | 0.67 |
| 4 or more | 20/92 (21.7%) | ||
|
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| Disease side | Right | 17/79 (21.5%) | 0.75 |
| Left | 20/102 (19.6%) | ||
|
| |||
| BMI | Less than 25 | 3/22 (13.6%) | |
| 25 or more | 34/151 (22.5%) | 0.43 | |
| Not reported | 0/8 (0%) | ||
|
| |||
| T stage | T1 | 17/87 (19.5%) | |
| T2 | 17/84 (20.2%) | 0.9 | |
| T3 | 3/10 (30%) | ||
Patients who received 2D radiotherapy had statistically significant higher incidence of lymphedema compared to patients who received 3DCRT (10/19 [55%] of patients in the 2D arm and 27/162 (16.6%) patients in the 3DCRT arm developed BCRL, p ≤ 0.001).
For the effect of type of radiotherapy fractionation, our data showed that patients who received hypofractionation had statistically significant less lymphedema (10/117 [8.5%] and 27/64 [42.2%] patients developed BCRL in the hypofractionation and conventional fractionation arm, respectively, p ≤ 0.001). There was no statistically significant difference in the rates of BCRL between the patients who had treatment interruptions versus patients who completed their treatment without interruption (Table 3). We did a subgroup analysis for the patients who underwent ALND only, and the results were almost the same (supplementary materials).
Table 3.
Effect of radiotherapy techniques and lymphedema
| Factor | Lymphedema | p value | |
|---|---|---|---|
| Type of radiotherapy | 2D | 10/19 (52.6%) | <0.001 |
| 3D | 27/162 (16.6%) | ||
|
| |||
| Radiotherapy fractionation | Conventional Hypofractionation | 27/64 (42.2%) 10/117 (8.5%) | <0.001 |
|
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| Treatment interruption | Yes | 21/104 (20.2%) | 1.0 |
| No | 16/77 (20.8%) | ||
|
| |||
| Days of interruption | 5 or less | 10/62 (16.1%) | 0.34 |
| More tdan 5 | 11/42 (26.2%) | ||
The dosimetric study showed that axillary levels received 81.7, 72.1, 74.7, 72.7, and 70.45% mean dose to level I, II, III, supraclavicular level, and axillary vessels, respectively, with no statistically significant correlation between the radiotherapy dose received and the development of BCRL (Table 4). Although, we could not find any significant correlation between the radiotherapy dose in Gray in both the hypofractionation and conventional fractionation arm and the development of BCRL.
Table 4.
Effect of radiotherapy dose
| A Effect of radiotherapy dose (by percent) of the axillary levels and vessels and the development of lymphedema in the whole cohort | ||||
|---|---|---|---|---|
| p value | T | Standardized coefficients beta | Mean, % | Axillary level |
| 0.995 | 0.007– | 0.1– | 81.74 | Mean RT dose level I |
| 0.58 | 0.558– | 0.52– | 72.1 | Mean RT dose level II |
| 0.92 | 0.107 | 0.1 | 74.71 | Mean RT dose level III |
| 0.93 | 0.087 | 0.007 | 72.77 | Mean RT dose supraclavicular |
| 0.21 | 1.27 | 0.18 | 70.45 | Mean RT dose axillary vessels |
| B Effect of radiotherapy dose (in Gray) of the axillary levels and vessels and the development of lymphedema in the conventional fractionation arm | ||||
|---|---|---|---|---|
| p value | T | Standardized coefficients beta | Mean dose, Gy | Axillary level |
| 0.08 | 1.733 | 0.224 | 37.39 | Mean RT dose level I |
| 0.212 | 1.263– | 0.165– | 36.32 | Mean RT dose level II |
| 0.836 | 0.208– | 0.028– | 35.79 | Mean RT dose level III |
| 0.473 | 0.722– | 0.095– | 36.72 | Mean RT dose supraclavicular |
| 0.817 | 0.233– | 0.031– | 34.77 | Mean RT dose axillary vessels |
| C Effect of radiotherapy dose (in Gray) of the axillary levels and vessels and the development of lymphedema in the hypofractionation arm | ||||
|---|---|---|---|---|
| p value | T | Standardized coefficients beta | Mean dose, Gy | Axillary level |
| 0.724 | 0.354 | 0.036 | 35.06 | Mean RT dose level I |
| 0.305 | 1.031 | 0.106 | 29.88 | Mean RT dose level II |
| 0.461 | 0.740 | 0.076 | 31.11 | Mean RT dose level III |
| 0.730 | 0.346 | 0.036 | 29.77 | Mean RT dose supraclavicular |
| 0.152 | 1.447 | 0.161 | 28.59 | Mean RT dose axillary vessels |
The multivariate analysis confirmed the significant correlation between the type of radiotherapy fractionation and the development of BCRL with a significantly higher rates in the conventional fractionation arm (p < 0.001) (Table 5).
Table 5.
Multivariate analysis for risk factors of BCRL
| Factor | p value | Odds ratio | 95% CI |
|
|---|---|---|---|---|
| lower | upper | |||
| Mean RT dose level I | 0.819 | 0.999 | 0.995 | 1.004 |
| Mean RT dose level II | 0.432 | 0.986 | 0.950 | 1.022 |
| Mean RT dose level III | 0.859 | 1.001 | 0.990 | 1.012 |
| Mean RT dose supraclavicular | 0.276 | 1.009 | 0.993 | 1.026 |
| Hypofractionation vs. conventional | <0.0001 | 0.078 | 0.026 | 0.239 |
| Treatment interruption | 0.499 | 0.688 | 0.233 | 2.032 |
| BMI | 0.164 | 4.620 | 0.535 | 39.899 |
Discussion
BCRL is one of the most bothersome side effects facing breast cancer patients which demands investigating its predisposing factors and the mechanisms by which we can decrease its incidence significantly. In our study, we tried to find a correlation between different radiotherapy risk factors and the development of BCRL. Insignificance of BMI and ALND versus SLNB which are known risk factors for lymphedema could be explained by the small number of patients with BMI <25 (12.1%) and SLNB (3.8%). The results showed significantly more lymphedema in patients who were treated with 2D compared to 3DCRT (despite the small number of patients) and in patients who received conventional fractionation radiotherapy compared to hypofractionation. Our data did not find significant correlation between the radiotherapy dose received by each axillary LN level as well as the axillary vessels and the development of BCRL, this may be due to the suboptimal mean dose received at each axillary level.
Treatment of breast cancer with radiotherapy in the 2D era was associated with many toxicities especially those with stochastic effects of radiotherapy, including BCRL which might be explained by the unexpected higher doses in breast tissue with or without regional nodes. This was elegantly shown by Ellen Donovan et al. [16] who reported higher radiotherapy hot areas in the patients who were treated with 2D compared to those who were treated with 3D IMRT plans.
The same observation was reported by Falahatpour et al. [17] who found a significantly higher mean hot dose areas in the 2D compared to the 3D plans. These data might explain our findings of the significantly higher incidence of BCRL in our cohorts who were treated with 2D-based radiotherapy. Most of the published data did not find significant difference in the incidence of BCRL in the patients who were treated with conventional compared to hypofractionated radiotherapy [13, 14] with only a small subset of patients in the start A and start B (13.8 and 6.9%, respectively) receiving RNI. While the data of hypofractionated RNI is less clear, a prospective trial that compared hypofractionated RNI with conventional radiotherapy has failed to show any significant difference in the rates of BCRL [18]. A larger retrospective data that came from Asia did not identify higher rates of arm edema with hypofractionated RNI [19]. Another prospective trial comparing conventional versus hypofractionated adjuvant radiotherapy in node-positive breast cancer, showed no difference between the 2 arms regarding the DFS and the toxicities including the BCRL [20]. Furthermore, a prospective study from India again did not find any statistically significant difference in the incidence of BCRL in hypofractionation and conventional fractionation arm [21]. Nevertheless, another study revealed a relatively low incidence of BCRL (5.8% developed grade 2 or more) in patients who received hypofractionated RNI [22]. All the previous limited data did not show significant difference between the 2 types fractionated radiotherapy and the incidence of BCRL. Moreover, our data projects a proposed detrimental effect of conventional fractionated radiotherapy and the development of lymphedema that might be explained as most of the patients who were treated using the 2D technique and who had ALND were treated with conventional radiotherapy.
Also, patients with higher nodal positivity were treated with conventional regimen. Considering the importance of this observation, more prospective randomized trials are warranted to confirm it.
Irradiation of the regional LNs when coupled with breast/chest wall radiotherapy significantly increases the risk of development of lymphedema. This finding was approved in many randomized trials [23, 24]. The question was, is there a correlation between radiotherapy dose to any of the LN levels including the SCV, IMN, axillary vessels or axillary LN levels I II and III? This correlation, if confirmed, might change our priorities and constraints to these areas trying to decrease the BCRL. Our data did not reveal significant correlation between the radiotherapy dose levels and the risk of BCRL. To our knowledge, this is the foremost data to study the correlation between the doses received by each axillary lymph node levels and the development of BCRL, and this observation needs to be studied in a larger prospective randomized trial as well.
Conclusion
The type and technique of radiotherapy to the axilla could affect the incidence of BCRL. According to our data, the 2D technique compared to the 3DCRT technique and conventional fractionated radiotherapy compared to hypofractionated radiotherapy significantly increases the risk of lymphedema. The radiotherapy dose received by axillary levels and axillary vessels did not show significant correlation with the development of BCRL. Accordingly, treating breast cancer patients with the 3DCRT technique and hypofractionation protocol might reduce the risk of BCRL.
Statement of Ethics
This study protocol was reviewed and approved by the ethics committee of Faculty of Medicine Alexandria University, approval number 00007555. A written informed consent was obtained from participants to participate in the study.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This research did not receive any specific grant from funding agencies.
Author Contributions
Mohamed Abouegylah: initiation of the project, mentoring the contouring, reviewing the results, writing the manuscript. Omnia Elemary: lymphedema measurements, contouring, data collection, follow up of the patients. Amr Munir: statistical analysis of the data and manuscript reviewing. Mohamed Y. Gouda: reviewing the results and the manuscript. Waleed O. Arafat: the corresponding author, reviewing the whole project and helping in writing and editing the manuscript. Sherif Elzawawy: methodology implantation, results reviewing, helping in writing and editing the manuscript.
Data Availability Statement
The data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.
Supplementary Material
Supplementary data
Acknowledgments
We thank our dosimetrists who participated in the project.
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Data Availability Statement
The data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.