- Email: [email protected]
Radiation Therapy Field Design and Lymphedema Risk After Regional Nodal Irradiation for Breast Cancer
Accepted Manuscript Radiotherapy Field Design and Lymphedema Risk Following Regional Nodal Irradiation for Breast Cancer Jeffrey P. Gross, MD, Sean Sachdev, MD, Irene B. Helenowski, PhD, David Lipps, PhD, John P. Hayes, MD, Eric D. Donnelly, MD, Jonathan B. Strauss, MD MBA PII:
S0360-3016(18)30597-2
DOI:
10.1016/j.ijrobp.2018.03.046
Reference:
ROB 24891
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 29 September 2017 Revised Date:
11 March 2018
Accepted Date: 26 March 2018
Please cite this article as: Gross JP, Sachdev S, Helenowski IB, Lipps D, Hayes JP, Donnelly ED, Strauss JB, Radiotherapy Field Design and Lymphedema Risk Following Regional Nodal Irradiation for Breast Cancer, International Journal of Radiation Oncology • Biology • Physics (2018), doi: 10.1016/ j.ijrobp.2018.03.046. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Radiotherapy Field Design and Lymphedema Risk Following Regional Nodal Irradiation for Breast Cancer Field design and lymphedema risk following RNI
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*Jeffrey P Gross, MD, *Sean Sachdev, MD, ꝉ Irene B Helenowski, PhD, ⱡDavid Lipps, PhD, *John P Hayes, MD, *Eric D Donnelly, MD, *Jonathan B Strauss MD MBA
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Statistical analyses: Irene B Helenowski, PhD 680 N. Lake Shore Drive, Suite 1400 Chicago, IL, 60611 E-mail address: [email protected] Phone: (312) 503-3597
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Departments of *Radiation Oncology and ꝉ Preventative Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. ⱡSchool of Kinesiology and Movement Science, University of Michigan, Ann Arbor, Michigan, USA.
Corresponding author: Jonathan B Strauss, MD MBA 251 E. Huron St, Galter Pavilion, LC-178 Chicago, IL, 60611 E-mail address: [email protected] Phone: (312) 926-2520
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Conflicts of Interest: There is no actual or potential conflict of interest with the production and submission of this work for publication. No author has direct or indirect commercial or financial incentive associated with the publication of this article.
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Acknowledgements: None
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Radiotherapy Field Design and Lymphedema Risk Following Regional Nodal Irradiation for
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Breast Cancer
3 Purpose:
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The occurrence of upper extremity lymphedema following regional nodal irradiation (RNI) for
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breast cancer treatment varies significantly based on patient and treatment factors. The
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relationship between radiotherapy field design and lymphedema risk is not well-characterized.
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This study sought to correlate variations in radiotherapy field design with lymphedema
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outcomes.
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10 Methods:
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Women with stage II-IV breast cancer receiving RNI following breast surgery including sentinel
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lymph node biopsy or axillary dissection were identified. Arm circumferences were measured
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prior to radiotherapy and at each follow-up to assess for lymphedema. Nodal radiotherapy fields
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were defined in a trifurcated system. Group 1 excluded the upper level I and II axilla, defined by
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lateral border of the nodal field encompassing less than one-third of the humeral head; Group 2
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included the upper level I and II axilla, defined by lateral border of the nodal field encompassing
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more than one-third of the humoral head treated with an anterior oblique beam; Group 3
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included the upper level I and II axilla just as Group 2, however with parallel-opposed beams
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delivering significant dose to the musculature posterior to the axilla.
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Results:
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Between 1999 and 2013, 526 women received RNI. Median post-radiotherapy follow-up was 5.5
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years. For 492 women meeting inclusion criteria, the cumulative incidence of lymphedema was
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23.5% at 2 years and 31.8% at 5 years. On univariate analysis, patients in group 1 had a lower
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5-year lymphedema rate (7.7%) compared to those in group 2 (37.1%) and group 3 (36.7%;
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p<0.0001). On multivariate analysis, inclusion of the upper level I and II axilla (Groups 2 and 3)
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remained significantly associated with increased lymphedema risk.
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Conclusion:
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Variations in radiotherapy field design significantly impact the development of lymphedema
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following RNI. In particular, the upper level I and II axilla appear to be important regions for
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lymphedema risk after axillary dissection.
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Funding: This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
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Introduction There is growing evidence that regional nodal irradiation (RNI) following either
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mastectomy or breast-conserving surgery decreases local-regional recurrence, subsequent risk
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of distant metastatic disease, and breast cancer mortality.1,2,15,16 However, RNI is associated
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with increased lymphedema risk which can significantly impair long-term quality of life3.
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Depending on the type of measurement used, prospective and retrospective series have found lymphedema rates following axillary dissection and RNI ranging from 9 – 65%4-6. Body mass
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index (BMI) and number of lymph nodes surgically removed have been consistently identified as
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contributing factors, but these factors alone cannot explain the wide variation in lymphedema
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rates4.
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A deeper understanding of the radiation-related factors contributing to lymphedema risk
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is crucial to both optimal field design and shared decision making about the potential benefits of
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RNI. However, several factors make it difficult to estimate lymphedema risk in the current era.
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First, the population of women with node-positive breast cancer eligible for RNI is
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heterogeneous and clinicians may define radiation targets differently based on judgement.
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Second, prior studies of lymphedema risk have measured the inclusion of RNI as a binary
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variable, making comparisons in technique impossible7. Finally, prior studies have considered
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differences in radiation beam arrangement such as inclusion of a posterior axillary boost (PAB),
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but not clearly delineated the volume of axillary tissue irradiated which may be more important
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for lymphedema development8,9.
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The present study hypothesized that field designs resulting in large volumes of axillary tissues being irradiated correlate with higher cumulative rates of lymphedema irrespective of
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beam arrangement. Therefore, the objective was to characterize different radiation field design
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as a function of the axillary volume irradiated, rather than beam arrangement alone. These
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detailed assessments of radiation technique were then compared with other known
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lymphedema risk factor to predict lymphedema outcomes.
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Materials and Methods
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This study was approved by the Institutional Review Board at our institution with waiver
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of informed consent due to its retrospective nature and limited risk. Women included in this
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study received surgery including breast conserving surgery (BCS) or mastectomy with sentinel
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lymph node biopsy (SNLB) or axillary dissection followed by RNI along with radiotherapy (RT) to
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the breast or chest wall. All patients were women with American Joint Committee on Cancer
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(AJCC) 7th edition stage II to IV breast cancer, Eastern Cooperative Oncology Group (ECOG)
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performance status 0 to 2, 18 years or older, and had complete medical records for assessment
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of outcomes. Patients who developed lymphedema prior to the initiation of RT or ≤ 3 months
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following surgery, had less than 1 year of post-RT follow-up, or incomplete treatment records
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were excluded.
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Patients were screened for lymphedema by measurement of arm circumference
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gathered prospectively by trained clinical staff as a standard component of clinical care.
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Measurements were taken following surgery at the time of initial RT consultation, during
treatment if there were clinical signs or symptoms, and routinely at each follow-up after the
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conclusion of RT, typically once every 3 months for the first 2 years, then every 4-6 months until
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year 5, then annually. Lymphedema was defined as difference in arm circumference on the
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treated side compared to the opposite ≥ 2.5 cm at any one encounter, or ≥ 2 cm on at least 2
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visits, when measured 15 cm above or 10 cm below the olecranon process10,11. To account for
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baseline asymmetries in arm circumference or post-surgical changes, arm measurements taken
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at initial consultation were treated as the baseline for each arm, and thus lymphedema was only
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diagnosed when arm circumference increased at subsequent visits. Additionally, any patients
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diagnosed with lymphedema after careful evaluation by a Physical Medicine and Rehabilitation
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specialist was classified as having lymphedema.
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RT plans were designed by one of nine radiation oncologists specializing in breast treatment at our institution during the study period. All radiation treatments were planned with
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Pinnacle treatment planning software (Phillips Healthcare), with treatment volumes contoured
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on axial CT images. All patients were treated in the supine position with the arm of the affected
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side abducted and externally rotated, with the head turned away from the treated breast or
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chest wall. Separate fields were used to treat the breast or chest wall which was matched to the
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supraclavicular (SCV) field. The RT plans were divided into three groups based on beam
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arrangement and 2-dimensional landmarks to simplify the classification into a trifurcated system.
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The classification scheme demonstrating radiation field design based on beam arrangement
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and volume of axillary tissue irradiated for each group is depicted in Figure 1 A-E. For each
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patient, a single Radiation Oncologist reviewed the digitally reconstructed radiograph (DRR)
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produced from the simulation CT scan, as well as treatment planning isodose lines to assign
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each patient a group based on precise assessment of the field design. Patients assigned to
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Group 1 had nodal field designs which excluded the upper level I and II axilla, defined as an
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anterior oblique beam with lateral border encompassing up to one-third of the humeral head,
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with or without inclusion of a small field posterior axillary boost (PAB) delivering ≤ 10% of the
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prescribed dose to musculature posterior to the axilla (Figure 1A and C). Patients assigned to
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Group 2 had nodal field designs that included the upper levels I, II, and III axilla, and the SCV
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fossa. This was defined as an anterior oblique beam with lateral border encompassing greater
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than one-third of the humeral head, with or without inclusion of a small field PAB delivering ≤
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10% of the prescribed dose to the musculature posterior to the axilla (Figure 1B and D). Finally,
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patients assigned to Group 3 were treated with parallel-opposed beams that each encompassed
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the entire field and included the upper levels I, II, and III axilla, and the SCV fossa; delivering >
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10% of the prescribed dose to the musculature posterior to the axilla (Figure 1E). Therefore,
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patients in Group 2 that were not treated with a PAB had minimal dose to the musculature
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posterior to the axilla, while those treated with a PAB had moderate dose. In contrast, patients
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in Group 3 had the highest doses delivered to the musculature posterior to the axilla.
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The primary endpoint was development of lymphedema following radiotherapy. Fisher’s exact tests were used to assess differences in categorical variables between groups and
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Wilcoxon rank sum tests were used to assess differences in continuous variables. Patient
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characteristics, tumor-related factors and treatment-related factors were all included in
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univariate analyses. Those variables that were statistically significant on univariate analysis
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were included into a Cox proportional hazards model for multivariate analysis. Cumulative
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incidence rates of lymphedema occurrence were estimated by group. Patients were censored at
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the time of last follow-up or death. Regional recurrences were included as a secondary
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endpoint, analyzed by the Kaplan-Meier method. They were also treated as competing risks in
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estimating cumulative incidence rates for lymphedema. Regional recurrences were defined as
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first recurrence in the ipsilateral axilla, SCV, or internal mammary (IM) lymph node without other
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evidence of systemic disease. For all measures, a p-value of less than 0.05 was considered
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statistically significant, with no adjustments for multiple testing. Analyses were performed with
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use of the SAS v9.4 (SAS Institute Inc., Cary, NC, USA.) and R 3.4.112 using the ggplot213 and
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survminer14 packages for plotting survival curves.
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Results
Between 1999 and 2013, 526 women who received RNI for stage II-VI breast cancer
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were identified. Of this cohort, 34 were excluded from the analysis, including 29 women who
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had not completed one year of post-RT follow-up and five women with incomplete treatment
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records. Patient, tumor, and treatment characteristics for the 492 women included in our final
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analyses are given in Table 1. The median post-RT follow-up was 5.5 years (interquartile range,
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3.6-7.6 years). The average number of follow-up visits where arm measurements were taken
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was 7 (range 1-13). There were no significant differences in patient handedness, breast
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surgery, side of breast/chest wall surgery, radiation dose to the whole breast, chest wall, or
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boost volume, or use of hormonal therapy between field design groups. There were small but
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statistically significant differences in T stage, use of chemotherapy either neoadjuvant or
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adjuvant, and radiation dose to the SCV fossa (Table 1). Overall, 71 patients (14.4%) received
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sentinel lymph node biopsy (SLNB) alone. More patients in Groups 2 and 3 had received SLNB
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compared to Group 1 [30 patients (14.9%) and 35 patients (18.5%), respectively vs. 6 patients
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(5.9%), p=0.014]. In addition, more patients in Groups 2 and 3 had extracapsular extension
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found on pathologic review compared to Group 1 (27.7% and 29.3%, respectively vs. 16.8%,
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p=0.05). By definition no patients in Group 3 received a posterior axillary boost (PAB), and more
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patients in Group 2 received PAB as compared to Group 1 (13.3% vs. 3%, p=0.004). Thirty-
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three patients treated by a single physician, classified as Group 1 based on the lateral border of
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the radiotherapy field, received a proportion of the dose from a posterior beam.
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The overall cumulative incidence of lymphedema was 16.9% at 2 years (95% confidence interval [CI], 13.8-20.5) and 24.9% at 5 years (95% CI, 21.2-29.1). Cumulative incidence of
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lymphedema per radiation field group is depicted in Figure 2. Women in Group 1 had the lowest
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cumulative incidence of lymphedema, 2% at 2 years (95% CI 0.51-7.9%) and 7.7% at 5 years
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(95% CI 3.7-15.5%). In comparison, women treated in Group 2 had 2-year rates of 26.9% (95%
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confidence interval [CI], 20.5-32.6) and 5-year rates of 37.1% (95% CI, 30.2-45.0) and women
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in Group 3 had 2-year rates of 28.6% (95% CI 22.4-35.2%) and 5-year rates of 36.7% (95% CI
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29.5-43.8, [p<0.0001]). For the limited number of patients that received SLNB only, zero of 6 in
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Group 1, 4 of 30 (13.3%) in Group 2, and 6 or 35 (17.1%) in Group 3 experienced lymphedema.
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On univariate analysis, factors associated with lymphedema included radiation field group, age
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at diagnosis, BMI at diagnosis, number of lymph nodes removed, and number of lymph nodes
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involved. Considering factors significant on univariate analysis, we constructed a Cox
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proportional hazards multivariable model utilizing radiation field group 1 as the reference. The
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results of the multivariable analyses are shown in Table 2. Radiation field Group 2 and Group 3
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were associated with lymphedema on multivariate analysis, HR 4.73 and 3.37 respectively. In
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addition, age at diagnosis (HR 1.02), BMI (HR 1.04), and number of lymph nodes sampled (HR
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1.03) were also associated with lymphedema risk (Table 2).
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To determine if certain clinical characteristics were predictive for choice of radiotherapy
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field design we performed a multivariable logistic regression including all clinical variables.
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Performance of SLNB was a negative predictor for treatment in Group 1 (OR 0.23, 95% CI 0.08-
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0.65, p=0.006). There were no significant clinical predictors for treatment in Group 2 versus 3,
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suggesting that this selection may have been based on the treating radiation oncologists’
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preferences.
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Regional and local-regional recurrences were infrequent. Overall, there were 8 regional only recurrences (1.63%) and 7 combined local-regional recurrences (1.42%). For patients
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treated with SLNB only versus axillary dissection, there were no statistically significant
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differences in regional recurrences (1 patient, 1.4%, versus 14 patients, 3.3%, p=0.62) or local-
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regional recurrences (3 patients, 4.2%, versus 22 patients, 5.2%, p=0.95). Similarly, there were
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no differences in regional recurrences for patients in radiation field group 1 (1 patient, 1.0%)
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versus field groups 2 or 3 (7 patients, 1.79%, p=0.99), or combined local-regional recurrences
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(4 patients, 4.0% versus 21 patients, 5.4%, p=0.75). Finally, there were no differences in overall
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survival (OS), local regional recurrence (LRR), or distant metastases (DM) between the groups.
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Survival curves based on the Kaplan-Meier method for OS, LRR and DM-free survival are
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presented in Figure 3.
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Discussion
The present study found that in the setting of axillary dissection, when the upper level I and II axilla were excluded from the nodal radiotherapy field, both 2- and 5-year lymphedema
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rates were significantly lower compared to when the upper level I and II axilla was irradiated.
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Furthermore, lymphedema rates were not significantly different for women whose radiation field
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extended beyond one-third of the humeral head laterally regardless of whether the dose was
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delivered through an anterior oblique beam, a posterior axillary boost (PAB) was added as a
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supplement, or parallel-opposed fields were used. These results were significant both in
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univariate and multivariate analysis and remained consistent throughout the study period. This
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suggests that extensive treatment to the upper level I and II axilla strongly predicts lymphedema
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risk, possibly due to the proximity of important arm lymphatic drainage pathways in this region.
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However, beam arrangement when evaluated independently of volume and distribution of
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axillary tissue irradiated is not predictive of lymphedema.
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Previous retrospective studies of lymphedema risk following RNI have mainly focused on
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details of field arrangement, such as whether a PAB was included. Hayes et al8 examined a
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cohort of 410 women receiving RNI (226 SCV fossa alone and 184 SCV and PAB). They found
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significantly higher rates of lymphedema in women who had treatment to the SCV (23%) but
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patients treated with SCV with a PAB field had equivalent rates (30.9%). A subgroup analysis of
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women with N2 disease did have higher rates of lymphedema if a PAB was added. Warren et
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al9 conducted a similar study in 194 women receiving RNI without a PAB versus 115 treated
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with a PAB and found no differences in lymphedema rates (21.9% and 21.1% respectively). Our
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study classified treatment fields based on the volume of axillary tissue irradiated and
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demonstrated that the posterior axilla included in the PAB field did not increase lymphedema
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risk after accounting for treatment to the upper level I and II axilla.
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Two recently published seminal randomized controlled trials also shed insight on how
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the volume of axillary tissue irradiated impacts lymphedema risk following RNI. The European
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Organization for Research and Treatment of Cancer (EORTC) 22922 study15 demonstrated that
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irradiation of the SCV and IM lymph nodes following lymph node dissection improved distant disease-free survival compared to treatment of the breast or chest wall alone. In this trial,
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irradiation excluded the level I and portions of the level II axilla per protocol. Of 1,922 women
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receiving RNI, 12% developed lymphedema compared to 10.5% of women who did not receive
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RNI and had axillary dissection alone. The National Cancer Institute of Canada (NCIC) MA.20
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study16, randomized 1,832 women to either whole breast radiotherapy plus RNI versus RNI
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alone following lymph node dissection. Per protocol, RNI included the level III axilla, SCV and
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IM lymph nodes. Unlike the EORTC trial, in MA.20 irradiation to the full axilla was mandated for
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a minority of women with limited dissections (fewer than 10 nodes identified) or the finding of 4
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or more involved nodes. For 893 women included in the long-term toxicity analysis, RNI was
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associated with significantly improved disease-free survival and relatively low rates of
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lymphedema (4.5% in the control arm versus 8.4% in women receiving RNI). Together the
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EORTC 22922 and NCIC MA.20 trials, as well as several retrospective series17,18, suggest that
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following axillary dissection lymphedema rates can be minimized with low rates of axillary
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recurrences, when axillary levels I and II are omitted from the RNI target volume. However, if
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there is a high burden of nodal disease such as ≥ 4 positive lymph nodes (per MA.20) or nodal
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metastases ≥ 2cm19, full axillary radiation may be considered.
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Finally, the interplay between axillary surgery, RT, and lymphedema risk has been
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clarified by two recent randomized trials. The American College of Surgeons Oncology Group
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(ACOSOG) Z011 trial, randomized women with clinically node-negative breast cancer and 1-2
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positive lymph nodes after SLNB to either completion axillary dissection versus observation and
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demonstrated non-inferiority to completion axillary dissection when followed by systemic therapy
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in 97% and whole breast radiation in 89.6%20. Low rates of lymphedema were reported in both
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arms, 13% overall for women receiving axillary dissection and 2% for women receiving SLNB
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alone21. The contribution of RT to lymphedema rates was unknown given the demonstrated
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inconsistencies and missing knowledge of RT field design, although per protocol radiation was
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directed to the whole breast only, some patients received formal RNI22. The EORTC AMAROS
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trial randomized women with clinical node negative axilla but pathologically positive sentinel
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lymph nodes to completion axillary dissection versus axillary irradiation23,24. Axillary RT yielded
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equivalent regional nodal control and overall survival while decreasing the rate of lymphedema
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defined by arm circumference compared to patients receiving completion axillary dissection (6%
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versus 13% at 5-years). This was also demonstrated in a subset of 44 patients from our study
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cohort comparable to those treated with axillary RT in the AMAROS trial (3 or fewer lymph
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nodes removed, treated with full axillary RT), 6 (13.6%) experienced lymphedema defined by
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arm measurements and clinical signs. It is important to emphasize that based on these data,
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following sentinel lymph node biopsy alone the entire axilla can be irradiated with low rates of
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lymphedema.
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Although the present study cohort was large and had long-term follow-up with
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prospective arm measurements, there are limitations to this analysis. First, there is no universal
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methodology measuring lymphedema. The chosen method for lymphedema monitoring in this
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study was measurement of arm circumference10,11. Although this method is widely used in
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practice, it may be subject to inter-rater variability. Other methods for volumetric measurement,
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such as use of a perometer, have been validated and may be preferable in settings where this is
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available25. Furthermore, this study classified lymphedema based on absolute arm
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measurement changes, but other studies have argued for the need to instead utilize relative
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changes in volume. Next, due to patterns of practice at our institution preoperative arm
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measurements were not available. Therefore, it is possible that pre-existing arm asymmetries
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may have biased the results leading to under- or over-diagnosis of lymphedema23. However,
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since in this study arm measurements taken post-operatively at the time of first radiation
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oncology consultation were not used to classify lymphedema, rather only subsequent increases
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in arm circumference following the completion of radiotherapy, this limitation may be less
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significant.
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In conclusion, in addition to other well-known risk factors for lymphedema following
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breast cancer treatment, the volume of axilla irradiated is significantly and independently
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associated with lymphedema. By contrast, the details of beam arrangement such as use of a
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PAB did not predict lymphedema risk. Omission of the upper level I and II axillary lymph nodes
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from the radiation treatment volume following axillary dissection confers a lower risk of
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lymphedema without increasing the risk of regional recurrence. However, surgical practices are
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evolving and in the present era more patients would likely have received SLNB without axillary
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dissection26. These data do not speak to this circumstance, and presently following SLNB
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patients require treatment to the full axilla. However, there is emerging evidence that techniques
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such as axillary reverse mapping (ARM) may reliably distinguish lymphatic pathways of the
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breast and upper arm27,28. The oncologic safety of sparing ARM-lymph nodes at the time of
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surgery, and whether this approach can reduce rates of lymphedema is currently being
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studied29,30. A detailed assessment of the inclusion of upper arm lymphatics in the RNI target
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volume should be the subject of future studies.
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13. Wickham H. ggplot2: elegant graphics for data analysis. Springer-Verlag New York, 2009.
14. Kassambra A and Kosinski M. survminer: drawing survival curves using ‘ggplot2’. 2017. R package version 0.4.0. https://CRAN.R-project.org/package=survminer 15. Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial
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Statistical Computing, Vienna, Austria. 2017. https://www.R-project.org/
supraclavicular irradiation in breast cancer. N Engl J Med 2015;373:317-27 16. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med 2015;373:307-16
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12. R Core Team. R: a language and environment for statistical computing. R Foundation for
17. Fowble B, Solin LJ, Schultz DJ, et al. Frequency, sites of relapse, and outcome of regional nodal failures following conservative surgery and radiation for early breast
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cancer. Int J Radiat Oncol Biol Phys 1989;6:109-116
18. Konkin DE, Tyldesley S, Kennecke H, et al. Management and outcomes of isolated axillary node recurrence in breast cancer. Arch Surg 2006;141:867-74
19. Grills IS, Kestin LL, Goldstein N, et al. Risk factors for regional nodal failure after breast-
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conserving therapy: regional nodal irradiation reduces rate of axillary failure in patients
25
with four or more positive lymph nodes. Int J Radat Oncol Biol Phys 2003;56(3):658-70
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20. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in
2
women with invasive breast cancer and sentinel node metastases. JAMA
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2011;305(6):569-75 21. Lucci A, McCall LM, Beitsch PD, et al. Surgical complications associated with sentinel
5
lymph node dissection (SLND) plus axillary lymph node dissection compared to SLND
6
alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol
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2007;25(24):3657-63
10
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22. Jagsi R, Chadha M, Moni J, et al. Radiation field design in the ACOSOG Z0011 (Alliance) trial. J Clin Oncol 2014;32(32):3600-06.
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23. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla
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after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a
12
randomized, multicenter, open-label, phase 3 non-inferiority trial. Lancet Oncol
13
2014;15:1303-10
24. Hurkmans CW, Borger JH, Rutgers EJ, et al. Quality assurance of axillary radiotherapy
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in the EORTC AMAROS trial 10981/22023: the dummy run. Radiother Oncol
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2003;68(3):233-40
25. Ancukiewica M, Russell TA, Otoole J, et al. Standardized method for quantification of
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developing lymphedema in patients treated for breast cancer. Int J Radiat Oncol Biol
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Phys 2011;79(5):1436-43
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26. Rescingo J, Zampell JC, Axelrod D, et al. Patterns of axillary surgical care for breast
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cancer in the era of sentinel lymph node biopsy. Ann Surg Oncol 2009;16(3):687-96
22
27. Boneti C, Korourian S, Diaz Z, et al. Axillary reverse mapping (ARM) to identify and
23
protect lymphatics draining the arm during axillary lymphadenectomy. Am J Surg
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2009;198(4):482-7
25 26
28. Nos C, Clough KB, Bonnier P, et al. Upper outer boundaries of the axillary dissection. Results of the SENTIBRAS protocol: multicentric protocol using axillary reverse mapping
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in breast cancer patients requiring axillary dissection. Eur J Surg Oncol
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2016;42(12):1827-33
3
29. Beek MA, Gobardhan PD, Schoenmaeckers EJ, et al. Axillary reverse mapping in axillary surgery for breast cancer: an update of the current status. Breast Cancer Res
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Treat 2016;158:421-32
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30. Tummel E, Ochoa D, Korourian S, et al. Does axillary reverse mapping prevent lymphedema after lymphadenectomy? Ann Surg 2017;265(5):987-92
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FIGURE CAPTIONS
2 Figure 1. 60-year-old woman with clinical T3N0 invasive ductal carcinoma ER+/PR-/Her2-
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status-post neoadjuvant chemotherapy and modified radical mastectomy and axillary dissection.
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Pathology revealed ypT2N1 disease, with 3 of 24 lymph nodes positive. (A) DRR representing
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design of beam as per Group 1. (B) DRR representing design as per Group 2. (C)
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Representative dose-distribution for Group 1. (D) Group 2, single anterior beam. (E) Group 3,
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parallel-opposed anterior-posterior beams weighted 3:1.
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Figure 2. Cumulative incidence of lymphedema by field group. Patients in field group 1 had
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lower lymphedema rates at 5 years compared to field groups 2 and 3, while there was no
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statistically significant difference in lymphedema rate between field groups 2 and 3.
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Figure 3. Kaplan-Meier curves illustrating (A) overall survival (OS), (B) distant metastasis (DM)-
15
free survival, and (C) local regional recurrences (LRR) by field group. There were no significant
16
differences when the upper level I and II axilla was omitted from the radiotherapy field design.
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Table 1. Patient, tumor, and treatment characteristics of the study cohort Radiation Field Group 1 (n = 101) 50 (40 - 59)
Characteristic Median age (IQR) – yr Median BMI (IQR)
Radiation Field Group 2 (n = 202) 50 (43 - 58)
Radiation Field Group 3 (n = 189) 50 (42 - 60)
p-value
28 (24 – 35)
<0.001
0.58
26 (23 - 31)
Breast surgery, No. (%) Lumpectomy Mastectomy
35 (34.7) 66 (65.3)
64 (31.7) 138 (68.3)
Axillary Surgery, No. (%) Sentinel LN biopsy only Axillary dissection
6 (5.9) 95 (94.1)
30 (14.9) 172 (85.1)
32 (31.7) 42 (41.5) 25 (24.8) 2 (2.0)
59 (29.2) 81 (40.1) 37 (18.3) 25 (12.4)
59 (31.2) 83 (43.9) 37 (19.6) 10 (5.3)
6 (5.9) 58 (57.4) 33 (32.7) 4 (4.0)
9 (4.5) 115 (56.9) 46 (22.8) 32 (15.8)
9 (4.8) 102 (53.9) 48 (25.4) 30 (15.9)
15 (12 - 19) 2 (1 - 5) 17 (16.8)
15 (9 - 20) 3 (1 - 6) 56 (27.7)
14 (8 - 19) 2 (1 - 6) 55 (29.3)
0.31 0.86 0.05
50.4 (48.6 - 50.4) 10 (6 - 14) 50.4 (46 - 50.4)
50.4 (50 - 50.4) 10 (10 - 14) 50.4 (50 - 50.4)
50.4 (45 - 50.4) 10 (10 - 14) 50.4 (50.4 - 50.4)
0.10 0.09 0.003
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Median No. of LNs excised (IQR) Median No. of positive LNs (IQR) Extra-nodal extension, No (%)
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Median Radiation Dose, Gy (IQR) Whole Breast/Chest Wall Whole Breast/Chest Wall Boost Supraclavicular Fossa Posterior axillary boost, No. (%)
0.03
0.07
Chemotherapy, No. (%) Neoadjuvant Adjuvant None
13 (12.9) 86 (85.1) 2 (2.0)
10 (5.0) 184 (91.0) 8 (4.0)
6 (3.2) 173 (91.5) 10 (5.3)
Hormone therapy, No. (%)
72 (71.3)
153 (75.7)
141 (74.6)
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27 (13.3)
th
0.014
35 (18.5) 154 (81.5)
3 (3.0)
*Based on AJCC, 7 edition ꝉ Comparison between Group 1 and Group 2
0.17
77 (40.7) 112 (59.3)
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Surgical features T stage*, No. (%) TX or T1 T2 T3 T4 N stage*, No. (%) pN0 pN1 pN2 pN3
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0 (0.0)
0.004 0.02
0.69
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Table 2. Multivariate cox regression model for lymphedema*
Hazard Ratio Variable
95% Confidence Limits
p-value
1.02
1.008-1.033
BMI at diagnosis (continuous)
1.04
1.01-1.06
0.007
Number of lymph nodes removed (continuous)
1.03
1.008-1.05
0.006
Radiation field group Field Group 2 Field Group 3
4.73 3.37
2.34-9.58 1.58-7.20
<0.0001 0.002
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*Radiation Field Group 1 as reference.
0.002
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Age at diagnosis (continuous)
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Considering the rising utilization of regional nodal irradiation for woman with nodepositive breast cancer, little is known about how the delivery of radiotherapy impacts lymphedema risk. This study characterized different field designs as a function of axillary volume irradiated to compare detailed assessment of radiation technique with other known risk factors for lymphedema. This study found that volume and distribution of axillary irradiation were important risk factors lymphedema, while beam arrangement alone was not.
S0360-3016(18)30597-2
DOI:
10.1016/j.ijrobp.2018.03.046
Reference:
ROB 24891
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 29 September 2017 Revised Date:
11 March 2018
Accepted Date: 26 March 2018
Please cite this article as: Gross JP, Sachdev S, Helenowski IB, Lipps D, Hayes JP, Donnelly ED, Strauss JB, Radiotherapy Field Design and Lymphedema Risk Following Regional Nodal Irradiation for Breast Cancer, International Journal of Radiation Oncology • Biology • Physics (2018), doi: 10.1016/ j.ijrobp.2018.03.046. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Radiotherapy Field Design and Lymphedema Risk Following Regional Nodal Irradiation for Breast Cancer Field design and lymphedema risk following RNI
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*Jeffrey P Gross, MD, *Sean Sachdev, MD, ꝉ Irene B Helenowski, PhD, ⱡDavid Lipps, PhD, *John P Hayes, MD, *Eric D Donnelly, MD, *Jonathan B Strauss MD MBA
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Statistical analyses: Irene B Helenowski, PhD 680 N. Lake Shore Drive, Suite 1400 Chicago, IL, 60611 E-mail address: [email protected] Phone: (312) 503-3597
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Departments of *Radiation Oncology and ꝉ Preventative Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. ⱡSchool of Kinesiology and Movement Science, University of Michigan, Ann Arbor, Michigan, USA.
Corresponding author: Jonathan B Strauss, MD MBA 251 E. Huron St, Galter Pavilion, LC-178 Chicago, IL, 60611 E-mail address: [email protected] Phone: (312) 926-2520
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Conflicts of Interest: There is no actual or potential conflict of interest with the production and submission of this work for publication. No author has direct or indirect commercial or financial incentive associated with the publication of this article.
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Acknowledgements: None
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Radiotherapy Field Design and Lymphedema Risk Following Regional Nodal Irradiation for
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Breast Cancer
3 Purpose:
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The occurrence of upper extremity lymphedema following regional nodal irradiation (RNI) for
6
breast cancer treatment varies significantly based on patient and treatment factors. The
7
relationship between radiotherapy field design and lymphedema risk is not well-characterized.
8
This study sought to correlate variations in radiotherapy field design with lymphedema
9
outcomes.
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Women with stage II-IV breast cancer receiving RNI following breast surgery including sentinel
13
lymph node biopsy or axillary dissection were identified. Arm circumferences were measured
14
prior to radiotherapy and at each follow-up to assess for lymphedema. Nodal radiotherapy fields
15
were defined in a trifurcated system. Group 1 excluded the upper level I and II axilla, defined by
16
lateral border of the nodal field encompassing less than one-third of the humeral head; Group 2
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included the upper level I and II axilla, defined by lateral border of the nodal field encompassing
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more than one-third of the humoral head treated with an anterior oblique beam; Group 3
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included the upper level I and II axilla just as Group 2, however with parallel-opposed beams
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delivering significant dose to the musculature posterior to the axilla.
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Results:
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Between 1999 and 2013, 526 women received RNI. Median post-radiotherapy follow-up was 5.5
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years. For 492 women meeting inclusion criteria, the cumulative incidence of lymphedema was
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23.5% at 2 years and 31.8% at 5 years. On univariate analysis, patients in group 1 had a lower
26
5-year lymphedema rate (7.7%) compared to those in group 2 (37.1%) and group 3 (36.7%;
27
p<0.0001). On multivariate analysis, inclusion of the upper level I and II axilla (Groups 2 and 3)
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remained significantly associated with increased lymphedema risk.
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Conclusion:
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Variations in radiotherapy field design significantly impact the development of lymphedema
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following RNI. In particular, the upper level I and II axilla appear to be important regions for
33
lymphedema risk after axillary dissection.
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Funding: This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.
3 4
Introduction There is growing evidence that regional nodal irradiation (RNI) following either
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mastectomy or breast-conserving surgery decreases local-regional recurrence, subsequent risk
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of distant metastatic disease, and breast cancer mortality.1,2,15,16 However, RNI is associated
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with increased lymphedema risk which can significantly impair long-term quality of life3.
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Depending on the type of measurement used, prospective and retrospective series have found lymphedema rates following axillary dissection and RNI ranging from 9 – 65%4-6. Body mass
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index (BMI) and number of lymph nodes surgically removed have been consistently identified as
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contributing factors, but these factors alone cannot explain the wide variation in lymphedema
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rates4.
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A deeper understanding of the radiation-related factors contributing to lymphedema risk
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is crucial to both optimal field design and shared decision making about the potential benefits of
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RNI. However, several factors make it difficult to estimate lymphedema risk in the current era.
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First, the population of women with node-positive breast cancer eligible for RNI is
18
heterogeneous and clinicians may define radiation targets differently based on judgement.
19
Second, prior studies of lymphedema risk have measured the inclusion of RNI as a binary
20
variable, making comparisons in technique impossible7. Finally, prior studies have considered
21
differences in radiation beam arrangement such as inclusion of a posterior axillary boost (PAB),
22
but not clearly delineated the volume of axillary tissue irradiated which may be more important
23
for lymphedema development8,9.
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The present study hypothesized that field designs resulting in large volumes of axillary tissues being irradiated correlate with higher cumulative rates of lymphedema irrespective of
26
beam arrangement. Therefore, the objective was to characterize different radiation field design
27
as a function of the axillary volume irradiated, rather than beam arrangement alone. These
28
detailed assessments of radiation technique were then compared with other known
29
lymphedema risk factor to predict lymphedema outcomes.
30
Materials and Methods
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This study was approved by the Institutional Review Board at our institution with waiver
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of informed consent due to its retrospective nature and limited risk. Women included in this
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study received surgery including breast conserving surgery (BCS) or mastectomy with sentinel
34
lymph node biopsy (SNLB) or axillary dissection followed by RNI along with radiotherapy (RT) to
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the breast or chest wall. All patients were women with American Joint Committee on Cancer
2
(AJCC) 7th edition stage II to IV breast cancer, Eastern Cooperative Oncology Group (ECOG)
3
performance status 0 to 2, 18 years or older, and had complete medical records for assessment
4
of outcomes. Patients who developed lymphedema prior to the initiation of RT or ≤ 3 months
5
following surgery, had less than 1 year of post-RT follow-up, or incomplete treatment records
6
were excluded.
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Patients were screened for lymphedema by measurement of arm circumference
8
gathered prospectively by trained clinical staff as a standard component of clinical care.
9
Measurements were taken following surgery at the time of initial RT consultation, during
treatment if there were clinical signs or symptoms, and routinely at each follow-up after the
11
conclusion of RT, typically once every 3 months for the first 2 years, then every 4-6 months until
12
year 5, then annually. Lymphedema was defined as difference in arm circumference on the
13
treated side compared to the opposite ≥ 2.5 cm at any one encounter, or ≥ 2 cm on at least 2
14
visits, when measured 15 cm above or 10 cm below the olecranon process10,11. To account for
15
baseline asymmetries in arm circumference or post-surgical changes, arm measurements taken
16
at initial consultation were treated as the baseline for each arm, and thus lymphedema was only
17
diagnosed when arm circumference increased at subsequent visits. Additionally, any patients
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diagnosed with lymphedema after careful evaluation by a Physical Medicine and Rehabilitation
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specialist was classified as having lymphedema.
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RT plans were designed by one of nine radiation oncologists specializing in breast treatment at our institution during the study period. All radiation treatments were planned with
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Pinnacle treatment planning software (Phillips Healthcare), with treatment volumes contoured
23
on axial CT images. All patients were treated in the supine position with the arm of the affected
24
side abducted and externally rotated, with the head turned away from the treated breast or
25
chest wall. Separate fields were used to treat the breast or chest wall which was matched to the
26
supraclavicular (SCV) field. The RT plans were divided into three groups based on beam
27
arrangement and 2-dimensional landmarks to simplify the classification into a trifurcated system.
28
The classification scheme demonstrating radiation field design based on beam arrangement
29
and volume of axillary tissue irradiated for each group is depicted in Figure 1 A-E. For each
30
patient, a single Radiation Oncologist reviewed the digitally reconstructed radiograph (DRR)
31
produced from the simulation CT scan, as well as treatment planning isodose lines to assign
32
each patient a group based on precise assessment of the field design. Patients assigned to
33
Group 1 had nodal field designs which excluded the upper level I and II axilla, defined as an
34
anterior oblique beam with lateral border encompassing up to one-third of the humeral head,
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with or without inclusion of a small field posterior axillary boost (PAB) delivering ≤ 10% of the
2
prescribed dose to musculature posterior to the axilla (Figure 1A and C). Patients assigned to
3
Group 2 had nodal field designs that included the upper levels I, II, and III axilla, and the SCV
4
fossa. This was defined as an anterior oblique beam with lateral border encompassing greater
5
than one-third of the humeral head, with or without inclusion of a small field PAB delivering ≤
6
10% of the prescribed dose to the musculature posterior to the axilla (Figure 1B and D). Finally,
7
patients assigned to Group 3 were treated with parallel-opposed beams that each encompassed
8
the entire field and included the upper levels I, II, and III axilla, and the SCV fossa; delivering >
9
10% of the prescribed dose to the musculature posterior to the axilla (Figure 1E). Therefore,
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patients in Group 2 that were not treated with a PAB had minimal dose to the musculature
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posterior to the axilla, while those treated with a PAB had moderate dose. In contrast, patients
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in Group 3 had the highest doses delivered to the musculature posterior to the axilla.
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The primary endpoint was development of lymphedema following radiotherapy. Fisher’s exact tests were used to assess differences in categorical variables between groups and
15
Wilcoxon rank sum tests were used to assess differences in continuous variables. Patient
16
characteristics, tumor-related factors and treatment-related factors were all included in
17
univariate analyses. Those variables that were statistically significant on univariate analysis
18
were included into a Cox proportional hazards model for multivariate analysis. Cumulative
19
incidence rates of lymphedema occurrence were estimated by group. Patients were censored at
20
the time of last follow-up or death. Regional recurrences were included as a secondary
21
endpoint, analyzed by the Kaplan-Meier method. They were also treated as competing risks in
22
estimating cumulative incidence rates for lymphedema. Regional recurrences were defined as
23
first recurrence in the ipsilateral axilla, SCV, or internal mammary (IM) lymph node without other
24
evidence of systemic disease. For all measures, a p-value of less than 0.05 was considered
25
statistically significant, with no adjustments for multiple testing. Analyses were performed with
26
use of the SAS v9.4 (SAS Institute Inc., Cary, NC, USA.) and R 3.4.112 using the ggplot213 and
27
survminer14 packages for plotting survival curves.
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Results
Between 1999 and 2013, 526 women who received RNI for stage II-VI breast cancer
31
were identified. Of this cohort, 34 were excluded from the analysis, including 29 women who
32
had not completed one year of post-RT follow-up and five women with incomplete treatment
33
records. Patient, tumor, and treatment characteristics for the 492 women included in our final
34
analyses are given in Table 1. The median post-RT follow-up was 5.5 years (interquartile range,
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3.6-7.6 years). The average number of follow-up visits where arm measurements were taken
2
was 7 (range 1-13). There were no significant differences in patient handedness, breast
3
surgery, side of breast/chest wall surgery, radiation dose to the whole breast, chest wall, or
4
boost volume, or use of hormonal therapy between field design groups. There were small but
5
statistically significant differences in T stage, use of chemotherapy either neoadjuvant or
6
adjuvant, and radiation dose to the SCV fossa (Table 1). Overall, 71 patients (14.4%) received
7
sentinel lymph node biopsy (SLNB) alone. More patients in Groups 2 and 3 had received SLNB
8
compared to Group 1 [30 patients (14.9%) and 35 patients (18.5%), respectively vs. 6 patients
9
(5.9%), p=0.014]. In addition, more patients in Groups 2 and 3 had extracapsular extension
10
found on pathologic review compared to Group 1 (27.7% and 29.3%, respectively vs. 16.8%,
11
p=0.05). By definition no patients in Group 3 received a posterior axillary boost (PAB), and more
12
patients in Group 2 received PAB as compared to Group 1 (13.3% vs. 3%, p=0.004). Thirty-
13
three patients treated by a single physician, classified as Group 1 based on the lateral border of
14
the radiotherapy field, received a proportion of the dose from a posterior beam.
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The overall cumulative incidence of lymphedema was 16.9% at 2 years (95% confidence interval [CI], 13.8-20.5) and 24.9% at 5 years (95% CI, 21.2-29.1). Cumulative incidence of
17
lymphedema per radiation field group is depicted in Figure 2. Women in Group 1 had the lowest
18
cumulative incidence of lymphedema, 2% at 2 years (95% CI 0.51-7.9%) and 7.7% at 5 years
19
(95% CI 3.7-15.5%). In comparison, women treated in Group 2 had 2-year rates of 26.9% (95%
20
confidence interval [CI], 20.5-32.6) and 5-year rates of 37.1% (95% CI, 30.2-45.0) and women
21
in Group 3 had 2-year rates of 28.6% (95% CI 22.4-35.2%) and 5-year rates of 36.7% (95% CI
22
29.5-43.8, [p<0.0001]). For the limited number of patients that received SLNB only, zero of 6 in
23
Group 1, 4 of 30 (13.3%) in Group 2, and 6 or 35 (17.1%) in Group 3 experienced lymphedema.
24
On univariate analysis, factors associated with lymphedema included radiation field group, age
25
at diagnosis, BMI at diagnosis, number of lymph nodes removed, and number of lymph nodes
26
involved. Considering factors significant on univariate analysis, we constructed a Cox
27
proportional hazards multivariable model utilizing radiation field group 1 as the reference. The
28
results of the multivariable analyses are shown in Table 2. Radiation field Group 2 and Group 3
29
were associated with lymphedema on multivariate analysis, HR 4.73 and 3.37 respectively. In
30
addition, age at diagnosis (HR 1.02), BMI (HR 1.04), and number of lymph nodes sampled (HR
31
1.03) were also associated with lymphedema risk (Table 2).
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To determine if certain clinical characteristics were predictive for choice of radiotherapy
33
field design we performed a multivariable logistic regression including all clinical variables.
34
Performance of SLNB was a negative predictor for treatment in Group 1 (OR 0.23, 95% CI 0.08-
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1
0.65, p=0.006). There were no significant clinical predictors for treatment in Group 2 versus 3,
2
suggesting that this selection may have been based on the treating radiation oncologists’
3
preferences.
4
Regional and local-regional recurrences were infrequent. Overall, there were 8 regional only recurrences (1.63%) and 7 combined local-regional recurrences (1.42%). For patients
6
treated with SLNB only versus axillary dissection, there were no statistically significant
7
differences in regional recurrences (1 patient, 1.4%, versus 14 patients, 3.3%, p=0.62) or local-
8
regional recurrences (3 patients, 4.2%, versus 22 patients, 5.2%, p=0.95). Similarly, there were
9
no differences in regional recurrences for patients in radiation field group 1 (1 patient, 1.0%)
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versus field groups 2 or 3 (7 patients, 1.79%, p=0.99), or combined local-regional recurrences
11
(4 patients, 4.0% versus 21 patients, 5.4%, p=0.75). Finally, there were no differences in overall
12
survival (OS), local regional recurrence (LRR), or distant metastases (DM) between the groups.
13
Survival curves based on the Kaplan-Meier method for OS, LRR and DM-free survival are
14
presented in Figure 3.
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15 16 17
Discussion
The present study found that in the setting of axillary dissection, when the upper level I and II axilla were excluded from the nodal radiotherapy field, both 2- and 5-year lymphedema
19
rates were significantly lower compared to when the upper level I and II axilla was irradiated.
20
Furthermore, lymphedema rates were not significantly different for women whose radiation field
21
extended beyond one-third of the humeral head laterally regardless of whether the dose was
22
delivered through an anterior oblique beam, a posterior axillary boost (PAB) was added as a
23
supplement, or parallel-opposed fields were used. These results were significant both in
24
univariate and multivariate analysis and remained consistent throughout the study period. This
25
suggests that extensive treatment to the upper level I and II axilla strongly predicts lymphedema
26
risk, possibly due to the proximity of important arm lymphatic drainage pathways in this region.
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However, beam arrangement when evaluated independently of volume and distribution of
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axillary tissue irradiated is not predictive of lymphedema.
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Previous retrospective studies of lymphedema risk following RNI have mainly focused on
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details of field arrangement, such as whether a PAB was included. Hayes et al8 examined a
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cohort of 410 women receiving RNI (226 SCV fossa alone and 184 SCV and PAB). They found
32
significantly higher rates of lymphedema in women who had treatment to the SCV (23%) but
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patients treated with SCV with a PAB field had equivalent rates (30.9%). A subgroup analysis of
34
women with N2 disease did have higher rates of lymphedema if a PAB was added. Warren et
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al9 conducted a similar study in 194 women receiving RNI without a PAB versus 115 treated
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with a PAB and found no differences in lymphedema rates (21.9% and 21.1% respectively). Our
3
study classified treatment fields based on the volume of axillary tissue irradiated and
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demonstrated that the posterior axilla included in the PAB field did not increase lymphedema
5
risk after accounting for treatment to the upper level I and II axilla.
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Two recently published seminal randomized controlled trials also shed insight on how
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the volume of axillary tissue irradiated impacts lymphedema risk following RNI. The European
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Organization for Research and Treatment of Cancer (EORTC) 22922 study15 demonstrated that
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irradiation of the SCV and IM lymph nodes following lymph node dissection improved distant disease-free survival compared to treatment of the breast or chest wall alone. In this trial,
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irradiation excluded the level I and portions of the level II axilla per protocol. Of 1,922 women
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receiving RNI, 12% developed lymphedema compared to 10.5% of women who did not receive
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RNI and had axillary dissection alone. The National Cancer Institute of Canada (NCIC) MA.20
14
study16, randomized 1,832 women to either whole breast radiotherapy plus RNI versus RNI
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alone following lymph node dissection. Per protocol, RNI included the level III axilla, SCV and
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IM lymph nodes. Unlike the EORTC trial, in MA.20 irradiation to the full axilla was mandated for
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a minority of women with limited dissections (fewer than 10 nodes identified) or the finding of 4
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or more involved nodes. For 893 women included in the long-term toxicity analysis, RNI was
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associated with significantly improved disease-free survival and relatively low rates of
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lymphedema (4.5% in the control arm versus 8.4% in women receiving RNI). Together the
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EORTC 22922 and NCIC MA.20 trials, as well as several retrospective series17,18, suggest that
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following axillary dissection lymphedema rates can be minimized with low rates of axillary
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recurrences, when axillary levels I and II are omitted from the RNI target volume. However, if
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there is a high burden of nodal disease such as ≥ 4 positive lymph nodes (per MA.20) or nodal
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metastases ≥ 2cm19, full axillary radiation may be considered.
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Finally, the interplay between axillary surgery, RT, and lymphedema risk has been
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clarified by two recent randomized trials. The American College of Surgeons Oncology Group
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(ACOSOG) Z011 trial, randomized women with clinically node-negative breast cancer and 1-2
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positive lymph nodes after SLNB to either completion axillary dissection versus observation and
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demonstrated non-inferiority to completion axillary dissection when followed by systemic therapy
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in 97% and whole breast radiation in 89.6%20. Low rates of lymphedema were reported in both
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arms, 13% overall for women receiving axillary dissection and 2% for women receiving SLNB
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alone21. The contribution of RT to lymphedema rates was unknown given the demonstrated
34
inconsistencies and missing knowledge of RT field design, although per protocol radiation was
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directed to the whole breast only, some patients received formal RNI22. The EORTC AMAROS
2
trial randomized women with clinical node negative axilla but pathologically positive sentinel
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lymph nodes to completion axillary dissection versus axillary irradiation23,24. Axillary RT yielded
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equivalent regional nodal control and overall survival while decreasing the rate of lymphedema
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defined by arm circumference compared to patients receiving completion axillary dissection (6%
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versus 13% at 5-years). This was also demonstrated in a subset of 44 patients from our study
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cohort comparable to those treated with axillary RT in the AMAROS trial (3 or fewer lymph
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nodes removed, treated with full axillary RT), 6 (13.6%) experienced lymphedema defined by
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arm measurements and clinical signs. It is important to emphasize that based on these data,
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following sentinel lymph node biopsy alone the entire axilla can be irradiated with low rates of
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lymphedema.
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Although the present study cohort was large and had long-term follow-up with
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prospective arm measurements, there are limitations to this analysis. First, there is no universal
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methodology measuring lymphedema. The chosen method for lymphedema monitoring in this
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study was measurement of arm circumference10,11. Although this method is widely used in
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practice, it may be subject to inter-rater variability. Other methods for volumetric measurement,
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such as use of a perometer, have been validated and may be preferable in settings where this is
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available25. Furthermore, this study classified lymphedema based on absolute arm
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measurement changes, but other studies have argued for the need to instead utilize relative
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changes in volume. Next, due to patterns of practice at our institution preoperative arm
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measurements were not available. Therefore, it is possible that pre-existing arm asymmetries
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may have biased the results leading to under- or over-diagnosis of lymphedema23. However,
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since in this study arm measurements taken post-operatively at the time of first radiation
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oncology consultation were not used to classify lymphedema, rather only subsequent increases
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in arm circumference following the completion of radiotherapy, this limitation may be less
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significant.
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In conclusion, in addition to other well-known risk factors for lymphedema following
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breast cancer treatment, the volume of axilla irradiated is significantly and independently
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associated with lymphedema. By contrast, the details of beam arrangement such as use of a
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PAB did not predict lymphedema risk. Omission of the upper level I and II axillary lymph nodes
31
from the radiation treatment volume following axillary dissection confers a lower risk of
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lymphedema without increasing the risk of regional recurrence. However, surgical practices are
33
evolving and in the present era more patients would likely have received SLNB without axillary
34
dissection26. These data do not speak to this circumstance, and presently following SLNB
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patients require treatment to the full axilla. However, there is emerging evidence that techniques
2
such as axillary reverse mapping (ARM) may reliably distinguish lymphatic pathways of the
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breast and upper arm27,28. The oncologic safety of sparing ARM-lymph nodes at the time of
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surgery, and whether this approach can reduce rates of lymphedema is currently being
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studied29,30. A detailed assessment of the inclusion of upper arm lymphatics in the RNI target
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volume should be the subject of future studies.
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REFERENCES 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTG). Effect of radiotherapy after
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breast-conserving surgery on 10-year recurrence and 15-year breast cancer death:
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Lancet (2011);378(9804):1707-16
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2. Recht A, Comen EA, Fine RE, et al. Postmastecomy radiotherapy: an American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical
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3. Kwan W, Jackson J, Weir LM. Chronic arm morbidity after curative breast cancer
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treatment: prevalence and impact on quality of life. J Clin Oncol (2002);20:4242-48 4. Shah C and Vicini FA. Breast-cancer related arm lymphedema: incidence rates,
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diagnostic techniques, optimal management and risk reduction strategies. Int J Radiat
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Oncol Biol Phys (2011);81(4):907-14
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5. DiSipio T, Rye S, Newman B, et al. Incidence of unilateral arm lymphedema after breast
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cancer: a systematic review and meta-analysis. Lancet Oncol (2013);14(6):500-15 6. Deutsch M, Land S, Begovic M, et al. The incidence of arm lymphedema in women with
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breast cancer randomized on the National Surgical Adjuvant Breast and Bowel Study B-
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04 to radical mastectomy versus total mastectomy and radiotherapy versus total
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mastectomy alone. Int J Radiat Oncol Biol Phys (2008);79:1020-24
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7. Gartner R, Jensen MB, Kronborg L, et al. Self-reported arm-lymphedema and functional impairment after breast cancer treatment- a nationwide study of prevalence and associated factors. Breast (2010);19:506-15
8. Hayes SB, Freedman GM, Li T, et al. Does axillary boost increase lymphedema
24
compared with supraclavicular radiation alone after breast conservation? Int J Radiat
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Oncol Biol Phys (2008);72(5):1449-55
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9. Warren L, Miller CL, Horick N, et al. The impact of radiation therapy on the risk of
2
lymphedema after treatment for breast cancer: a prospective cohort study. Int J Radiat
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Oncol Biol Phys (2013);88(3):565-71
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10. Armer JM and Stewart BR. A comparison of four diagnostic criteria for lymphedema in a
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post-breast cancer population. Lymphat Res Biol (2005); 3(4):208–217
11. Position Statement of the National Lymphedema Network. Topic: Screening and
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Measurement for Early Detection of Breast Cancer Related Lymphedema (2013)
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13. Wickham H. ggplot2: elegant graphics for data analysis. Springer-Verlag New York, 2009.
14. Kassambra A and Kosinski M. survminer: drawing survival curves using ‘ggplot2’. 2017. R package version 0.4.0. https://CRAN.R-project.org/package=survminer 15. Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial
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Statistical Computing, Vienna, Austria. 2017. https://www.R-project.org/
supraclavicular irradiation in breast cancer. N Engl J Med 2015;373:317-27 16. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med 2015;373:307-16
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12. R Core Team. R: a language and environment for statistical computing. R Foundation for
17. Fowble B, Solin LJ, Schultz DJ, et al. Frequency, sites of relapse, and outcome of regional nodal failures following conservative surgery and radiation for early breast
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cancer. Int J Radiat Oncol Biol Phys 1989;6:109-116
18. Konkin DE, Tyldesley S, Kennecke H, et al. Management and outcomes of isolated axillary node recurrence in breast cancer. Arch Surg 2006;141:867-74
19. Grills IS, Kestin LL, Goldstein N, et al. Risk factors for regional nodal failure after breast-
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conserving therapy: regional nodal irradiation reduces rate of axillary failure in patients
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with four or more positive lymph nodes. Int J Radat Oncol Biol Phys 2003;56(3):658-70
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20. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in
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women with invasive breast cancer and sentinel node metastases. JAMA
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2011;305(6):569-75 21. Lucci A, McCall LM, Beitsch PD, et al. Surgical complications associated with sentinel
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lymph node dissection (SLND) plus axillary lymph node dissection compared to SLND
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alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol
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2007;25(24):3657-63
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22. Jagsi R, Chadha M, Moni J, et al. Radiation field design in the ACOSOG Z0011 (Alliance) trial. J Clin Oncol 2014;32(32):3600-06.
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23. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla
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after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a
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randomized, multicenter, open-label, phase 3 non-inferiority trial. Lancet Oncol
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2014;15:1303-10
24. Hurkmans CW, Borger JH, Rutgers EJ, et al. Quality assurance of axillary radiotherapy
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in the EORTC AMAROS trial 10981/22023: the dummy run. Radiother Oncol
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2003;68(3):233-40
25. Ancukiewica M, Russell TA, Otoole J, et al. Standardized method for quantification of
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developing lymphedema in patients treated for breast cancer. Int J Radiat Oncol Biol
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Phys 2011;79(5):1436-43
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26. Rescingo J, Zampell JC, Axelrod D, et al. Patterns of axillary surgical care for breast
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cancer in the era of sentinel lymph node biopsy. Ann Surg Oncol 2009;16(3):687-96
22
27. Boneti C, Korourian S, Diaz Z, et al. Axillary reverse mapping (ARM) to identify and
23
protect lymphatics draining the arm during axillary lymphadenectomy. Am J Surg
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2009;198(4):482-7
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28. Nos C, Clough KB, Bonnier P, et al. Upper outer boundaries of the axillary dissection. Results of the SENTIBRAS protocol: multicentric protocol using axillary reverse mapping
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in breast cancer patients requiring axillary dissection. Eur J Surg Oncol
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2016;42(12):1827-33
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29. Beek MA, Gobardhan PD, Schoenmaeckers EJ, et al. Axillary reverse mapping in axillary surgery for breast cancer: an update of the current status. Breast Cancer Res
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Treat 2016;158:421-32
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30. Tummel E, Ochoa D, Korourian S, et al. Does axillary reverse mapping prevent lymphedema after lymphadenectomy? Ann Surg 2017;265(5):987-92
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FIGURE CAPTIONS
2 Figure 1. 60-year-old woman with clinical T3N0 invasive ductal carcinoma ER+/PR-/Her2-
4
status-post neoadjuvant chemotherapy and modified radical mastectomy and axillary dissection.
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Pathology revealed ypT2N1 disease, with 3 of 24 lymph nodes positive. (A) DRR representing
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design of beam as per Group 1. (B) DRR representing design as per Group 2. (C)
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Representative dose-distribution for Group 1. (D) Group 2, single anterior beam. (E) Group 3,
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parallel-opposed anterior-posterior beams weighted 3:1.
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Figure 2. Cumulative incidence of lymphedema by field group. Patients in field group 1 had
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lower lymphedema rates at 5 years compared to field groups 2 and 3, while there was no
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statistically significant difference in lymphedema rate between field groups 2 and 3.
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Figure 3. Kaplan-Meier curves illustrating (A) overall survival (OS), (B) distant metastasis (DM)-
15
free survival, and (C) local regional recurrences (LRR) by field group. There were no significant
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differences when the upper level I and II axilla was omitted from the radiotherapy field design.
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Table 1. Patient, tumor, and treatment characteristics of the study cohort Radiation Field Group 1 (n = 101) 50 (40 - 59)
Characteristic Median age (IQR) – yr Median BMI (IQR)
Radiation Field Group 2 (n = 202) 50 (43 - 58)
Radiation Field Group 3 (n = 189) 50 (42 - 60)
p-value
28 (24 – 35)
<0.001
0.58
26 (23 - 31)
Breast surgery, No. (%) Lumpectomy Mastectomy
35 (34.7) 66 (65.3)
64 (31.7) 138 (68.3)
Axillary Surgery, No. (%) Sentinel LN biopsy only Axillary dissection
6 (5.9) 95 (94.1)
30 (14.9) 172 (85.1)
32 (31.7) 42 (41.5) 25 (24.8) 2 (2.0)
59 (29.2) 81 (40.1) 37 (18.3) 25 (12.4)
59 (31.2) 83 (43.9) 37 (19.6) 10 (5.3)
6 (5.9) 58 (57.4) 33 (32.7) 4 (4.0)
9 (4.5) 115 (56.9) 46 (22.8) 32 (15.8)
9 (4.8) 102 (53.9) 48 (25.4) 30 (15.9)
15 (12 - 19) 2 (1 - 5) 17 (16.8)
15 (9 - 20) 3 (1 - 6) 56 (27.7)
14 (8 - 19) 2 (1 - 6) 55 (29.3)
0.31 0.86 0.05
50.4 (48.6 - 50.4) 10 (6 - 14) 50.4 (46 - 50.4)
50.4 (50 - 50.4) 10 (10 - 14) 50.4 (50 - 50.4)
50.4 (45 - 50.4) 10 (10 - 14) 50.4 (50.4 - 50.4)
0.10 0.09 0.003
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Median No. of LNs excised (IQR) Median No. of positive LNs (IQR) Extra-nodal extension, No (%)
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Median Radiation Dose, Gy (IQR) Whole Breast/Chest Wall Whole Breast/Chest Wall Boost Supraclavicular Fossa Posterior axillary boost, No. (%)
0.03
0.07
Chemotherapy, No. (%) Neoadjuvant Adjuvant None
13 (12.9) 86 (85.1) 2 (2.0)
10 (5.0) 184 (91.0) 8 (4.0)
6 (3.2) 173 (91.5) 10 (5.3)
Hormone therapy, No. (%)
72 (71.3)
153 (75.7)
141 (74.6)
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th
0.014
35 (18.5) 154 (81.5)
3 (3.0)
*Based on AJCC, 7 edition ꝉ Comparison between Group 1 and Group 2
0.17
77 (40.7) 112 (59.3)
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Surgical features T stage*, No. (%) TX or T1 T2 T3 T4 N stage*, No. (%) pN0 pN1 pN2 pN3
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0 (0.0)
0.004 0.02
0.69
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Table 2. Multivariate cox regression model for lymphedema*
Hazard Ratio Variable
95% Confidence Limits
p-value
1.02
1.008-1.033
BMI at diagnosis (continuous)
1.04
1.01-1.06
0.007
Number of lymph nodes removed (continuous)
1.03
1.008-1.05
0.006
Radiation field group Field Group 2 Field Group 3
4.73 3.37
2.34-9.58 1.58-7.20
<0.0001 0.002
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Age at diagnosis (continuous)
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Considering the rising utilization of regional nodal irradiation for woman with nodepositive breast cancer, little is known about how the delivery of radiotherapy impacts lymphedema risk. This study characterized different field designs as a function of axillary volume irradiated to compare detailed assessment of radiation technique with other known risk factors for lymphedema. This study found that volume and distribution of axillary irradiation were important risk factors lymphedema, while beam arrangement alone was not.