This study was conducted to evaluate the impact of supraclavicular lymph node radiotherapy (SCNRT) on N1 breast cancer patients receiving post-lumpectomy whole-breast irradiation (WBI) and anthracycline plus taxane-based (AT) chemotherapy.
We performed a case-control analysis to compare the outcomes of WBI and WBI plus SCNRT (WBI+SCNRT). Among 1,147 patients with N1 breast cancer who received post-lumpectomy radiotherapy and AT-based chemotherapy in 12 hospitals, 542 were selected after propensity score matching. Patterns of failure, disease-free survival (DFS), distant metastasis-free survival (DMFS), and treatment-related toxicity were compared between groups.
A total of 41 patients (7.6%) were found to have recurrence. Supraclavicular lymph node (SCN) failure was detected in three patients, two in WBI and one in WBI+SCNRT. All SCN failures were found simultaneously with distant metastasis. There was no significant difference in patterns of failure or survival between groups. The 5-year DFS and DMFS for patients with WBI and WBI+SCNRT were 94.4% versus 92.6% (p=0.50) and 95.1% versus 94.5% (p=0.99), respectively. The rates of lymphedema and radiation pneumonitis were significantly higher in the WBI+SCNRT than in the WBI.
We did not find a benefit of SCNRT for N1 breast cancer patients receiving AT-based chemotherapy.
Post-mastectomy radiotherapy (PMRT) of the regional lymph nodes and chest wall is associated with reduced locoregional recurrence and improved survival in patients with node-positive breast cancer [
Regarding the extent of RNI for N1 breast cancer, it is not yet known which regional lymph nodes should be included in post-lumpectomy radiotherapy. In the aforementioned trials and studies of PMRT [
The present study was conducted to investigate the prognostic impact of elective SCNRT in N1 breast cancer patients who received systemic treatments, including anthracycline plus taxane-based (AT) chemotherapy. We compared treatment outcomes and complications between the two treatment groups, WBI alone versus WBI plus SCNRT (WBI+SCNRT), to determine if elective SCNRT is beneficial for N1 breast cancer patients in an era of effective systemic treatments.
To compare treatment outcomes between groups, WBI alone versus WBI+SCNRT, we conducted a matched casecontrol study of patients with N1 breast cancer using patient data from 12 hospitals that are members of the Korean Radiation Oncology Group (KROG). Patients who underwent AT chemotherapy and post-lumpectomy radiotherapy for N1 breast cancer between January 2006 and December 2010 were included in this study. The inclusion criteria were patients with N1 breast cancer who received breast conservingsurgery (BCS) and axillary lymph node dissection (ALND), those who completed postoperative AT chemotherapy and radiotherapy as planned, and those for whom information regarding pathological features of the tumor was available. The exclusion criteria were patients who received neoadjuvant chemotherapy, chemotherapy other than AT, or IMN radiotherapy. The Institutional Review Board of each participating hospital approved the current study.
The collected patient data were pathologic features of each tumor such as tumor size, number of positive lymph nodes, histologic grade (HG), presence of lymphovascular invasion (LVI), and expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). ER/PR positivity was defined as a 3 to 8 Allred score by immunohistochemistry (IHC). HER2 positivity was defined as either staining 3+ by IHC or 2+ by IHC with positive fluorescence
All patients received BCS and ALND with or without sentinel lymph node evaluation. Doxorubicin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) followed by paclitaxel or docetaxel (T) were prescribed to all patients. According to the hormonal receptor or HER2 positivity of each tumor, adjuvant endocrine therapy or anti-HER2 agent was administered. WBI and tumor bed boost were given to all patients. The decision regarding whether to administer elective SCNRT to patients was made according to institutional policies across the 12 participating hospitals. Pathologic features such as high HG, positive LVI, large numbers of metastatic lymph nodes, or non-luminal subtypes were high-risk factors that influence the decision of whether to add SCNRT to WBI.
The doses for whole breast and tumor bed were 45.0-60.4 Gy at 1.8-3.0 Gy per fraction and 4.0-19.8 Gy at 1.8-3.5 Gy per fraction, respectively. Conventionally fractionated WBI with a daily dose of 1.8-2.0 Gy was performed in 512 patients (94.5%), while hypofractionated WBI with a total dose of 51.0 Gy in 17 fractions at 3.0 Gy per fraction was delivered to 30 patients (5.5%). The radiation dose to SCN was 45.0-50.4 Gy at 1.8-2.0 Gy per fraction. Borders of each field of WBI or WBI+SCNRT were variously defined in the 12 hospitals according to each institutional policy. Nevertheless, there were common principles of beam configuration. The superior, inferior, and lateral borders of the field of WBI were 2 cm beyond the palpable breast tissue. The medial border was located at midline, and the superficial border allowed 2 cm of flash beyond the breast. The superior, inferior, lateral, and medial borders of the field of SCNRT were the upper border of the supraclavicular fossa, match line of tangential beams of WBI, lateral edge of clavicle, and 0.5 cm from the spinal cord. ALNs were not intentionally irradiated. Nonetheless, level I and some portion of level II ALNs were covered during WBI while a part of level II and III ALNs and the SCN were irradiated during SCNRT.
Treatment related toxicity was graded by the Common Terminology Criteria for Adverse Events, ver. 3.0 [
Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) were defined as the interval from surgery to death, cancer recurrence, loco-regional recurrence, and distant metastasis, respectively. Among the variables, number of tumors, LVI, HG, and hormone receptor status were considered as binary variables. Patient age, tumor size, number of positive nodes, and ratio of positive nodes were analyzed as continuous variables. An optimal cut-off of continuous variables was defined using analysis of the area under the curve of receiver operating characteristics. The value for which sensitivity and specificity were the highest was chosen as the optimal cut-off point for each variable. The chi-square test or Fisher exact test was used to compare the patient characteristics between the two groups. Survival probability was estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival between groups with different variables. To determine the independent prognostic factors for the outcomes, Cox regression analysis with stepwise selection was used. A two sided p-value of < 0.05 was assumed as statistically significant.
To maintain a balance of covariates between the two treatment groups, one-to-one matching was performed on the basis of the propensity scores of each patient. As matching variables, we selected tumor size, LVI, HG, and ratio of positive lymph nodes. These variables were identified as significant prognostic factors for patient survival in the primary data set (
A total of 1,147 patients met the inclusion criteria of the current study. The 5-year rates of DFS, OS, LRRFS, and DMFS of 1,147 patients were 93.0%, 98.5%, 97.3%, and 94.2%, respectively. Among the 1,147 patients, 783 had WBI alone, while 364 received WBI+SCNRT. The 5-year DFS rate was 93.1% for patients with WBI, while it was 92.6% for patients with WBI+SCNRT (p=0.79) (
The median age of the patients was 47 years (range, 26 to 69 years). All patients had a clear resection margin on their surgical specimen. The median tumor size was 20 mm (range 0.1 to 51 mm). All but two patients had T1 or T2 stage tumor. The median number of examined lymph nodes was 16 (range, 2 to 48). Among the 414 patients with hormone receptor–positive tumors, 384 (92.8%) were treated with endocrine therapy. In 105 patients with HER2 amplified tumors, anti-HER2 agent was given to 28 (26.7%). Details regarding the patient characteristics are shown in
The median follow-up times of the patients with WBI alone and WBI+SCNRT were 73 months (range, 10 to 111 months) and 60 months (range, 12 to 111 months), respectively. A total of 41 patients (7.6%) were found to have disease recurrence. Patterns of the first failure were not significantly different between the two groups (
The rates of lymphedema and radiation pneumonitis were significantly higher in patients with SCNRT than in those without SCNRT (
In this case-control study, we evaluated the prognostic impact of elective SCNRT in post-lumpectomy radiotherapy for N1 breast cancer. We found that there was no benefit of the addition of SCNRT in patients treated with contemporary systemic treatments including AT chemotherapy. Treatment outcomes with respect to loco-regional and distant tumor control were not significantly different between the WBI alone group and the WBI+SCNRT group. The addition of SCNRT to WBI was associated with increased risk of lymphedema and radiation-related pneumonitis compared with WBI alone. Therefore, we suggest that elective SCNRT is not an essential component in post-lumpectomy radiotherapy for N1 breast cancer in patients receiving AT-based chemotherapy.
In patients with early breast cancer, RNI is added to WBI to control microscopic regional nodal disease and prevent systemic spread of cancer by sterilizing subclinical disease in the regional lymph nodes [
A large portion of the lymphatics from the breast pass through the ALN to SCN or drain to the IMN. There is direct nodal drainage to the SCN without traversing the ALN [
In this study, we assessed the benefit of elective SCNRT in N1 breast cancer patients treated with the current standard systemic treatments. All patients were given AT-based chemotherapy, and over 92% of patients with hormoneresponsive breast cancer received adjuvant endocrine therapy. We found that, regardless of elective SCNRT, SCN metastases occurred in less than 1% of patients with N1 breast cancer when they were treated with post-lumpectomy WBI, AT-based chemotherapy, and systemic agents according to the molecular subtype of the tumor. All SCN failures were found simultaneously with distant sites metastases. Moreover, we did not observe any significant change in patient survival or pattern of the first failure in response to the addition of SCNRT. According to previous studies, administering AT-based chemotherapy reduced disease recurrence and breast cancer mortality more effectively than applying an anthracycline-based regimen alone for patients with early breast cancer [
There is a possibility that microscopic tumor burden in the SCN area is not sufficient to bring benefits by the addition of SCNRT in N1 breast cancer. According to a study describing patterns of lymphatic drainage of breast cancer by sentinel lymph node mappings, only 0.5% of patients with clinically node-negative breast cancer had sentinel lymph node metastasis in the SCN area [
We found that lymphedema and pneumonitis occurred more frequently after WBI+SCNRT than after WBI alone. In the current study, about 16% of patients showed lymphedema after WBI+SCNRT. ALND, which was performed on all patients in this study, might contribute to the risk of lymphedema. Previous studies reported that arm edema was found in 3%-25% of patients with ALND, WBI, or SCNRT [
It should be noted that our study had several limitations. Specifically, there might have been biases in selecting patients because patient data were retrospectively collected and matched in this study. We balanced probable prognostic factors of patients between the two treatment groups by matching propensity score; however, unperceived variables might have been unevenly distributed between groups. Additionally, pathologic examinations were conducted at several different hospitals in this study, thereby causing missing information regarding some pathologic characteristics of the tumors. For example, not all participating hospitals were able to provide information describing extracapsular extensions of metastatic lymph nodes or Ki-67 levels. Therefore, it is possible that the pathologic variables could have been arranged unequally between the treatment groups. Finally, the duration of follow-up of patients was relatively short in this study. The median follow-up period was 73 months for patients with WBI and 60 months for those with WBI+SCNRT. It has been reported that long-term follow-up is necessary for patients with breast cancer to detect late disease recurrence and treatment-related adverse effects [
In this study, we could not determine a subgroup of patients who benefitted from elective SCNRT. There were no pathologic features or molecular subtypes significantly associated with improved outcome by the addition of SCNRT. It was recently reported that the gene expression profile of a tumor can predict loco-regional recurrence and distant metastasis of breast cancer [
In conclusion, elective SCNRT did not provide an advantage for tumor control in patients with N1 breast cancer when they received effective systemic treatments. Mild treatment-related complications were found more frequently following the addition of SCNRT. Further randomized studies are necessary to determine the optimal field of post-lumpectomy radiotherapy for N1 breast cancer.
Supplementary materials are available at Cancer Research and Treatment website (
Conflict of interest relevant to this article was not reported.
Survival according to radiation field. Disease-free survival (A), loco-regional recurrence-free survival (LRRFS) (B), distant metastasis-free survival (DMFS) (C), and overall survival (D) are shown. WBI, whole-breast irradiation; SCNRT, supraclavicular lymph node radiotherapy.
Comparison of patient characteristics between groups
Characteristic | Before matching |
After matching |
||||
---|---|---|---|---|---|---|
WBI alone (n=783) | WBI+SCNRT (n=364) | p-value | WBI alone (n=271) | WBI+SCNRT (n=271) | p-value | |
≤ 40 | 151 (19.3) | 80 (21.9) | 0.29 | 47 (17.3) | 57 (21.1) | 0.27 |
> 40 | 632 (80.7) | 284 (78.1) | 224 (82.7) | 214 (78.9) | ||
IDC | 745 (95.1) | 333 (91.5) | 0.02 | 260 (95.9) | 254 (93.7) | 0.24 |
Non-IDC | 38 (4.9) | 31 (8.5) | 11 (4.1) | 17 (6.3) | ||
≤ 20 | 406 (51.9) | 182 (50.0) | 0.56 | 127 (46.8) | 127 (46.8) | 1.00 |
> 20 | 377 (48.1) | 182 (50.0) | 144 (53.2) | 144 (53.2) | ||
T1 | 397 (50.7) | 172 (47.3) | 0.32 | 125 (46.1) | 123 (45.4) | 0.99 |
T2 | 382 (48.8) | 188 (51.6) | 145 (53.5) | 147 (54.2) | ||
T3 | 4 (0.5) | 4 (1.1) | 1 (0.4) | 1 (0.4) | ||
Single | 652 (83.3) | 302 (82.9) | 0.89 | 226 (83.4) | 227 (83.7) | 0.91 |
Multiple | 131 (16.7) | 62 (17.1) | 45 (16.6) | 44 (16.3) | ||
Negative | 368 (46.9) | 85 (23.4) | < 0.01 | 80 (29.5) | 80 (29.5) | 1.00 |
Positive | 415 (53.1) | 279 (76.6) | 191 (70.5) | 191 (70.5) | ||
1, 2 | 488 (62.3) | 225 (61.8) | 0.86 | 159 (58.7) | 159 (58.7) | 1.00 |
3 | 295 (37.7) | 139 (38.2) | 112 (41.3) | 112 (41.3) | ||
Luminal A | 415 (53.1) | 180 (49.5) | 0.04 | 136 (50.1) | 125 (46.1) | 0.20 |
Luminal B | 127 (16.2) | 53 (14.6) | 46 (16.9) | 42 (15.5) | ||
Luminal-HER2 | 66 (8.4) | 51 (14.0) | 26 (9.6) | 39 (14.4) | ||
HER2 enriched | 51 (6.5) | 18 (4.9) | 24 (8.9) | 16 (5.9) | ||
Triple negative | 124 (15.8) | 62 (17.0) | 39 (14.5) | 49 (18.1) | ||
1 | 550 (70.2) | 118 (32.4) | < 0.01 | 114 (42.1) | 114 (42.1) | 1.00 |
2 | 161 (20.6) | 144 (39.6) | 97 (35.8) | 97 (35.8) | ||
3 | 72 (9.2) | 102 (28.0) | 60 (22.1) | 60 (22.1) | ||
≤ 16 | 437 (55.8) | 210 (57.7) | 0.55 | 145 (53.5) | 144 (53.1) | 0.93 |
> 16 | 346 (44.2) | 154 (42.3) | 126 (46.5) | 127 (46.9) | ||
≤ 0.1 | 546 (69.7) | 147 (40.4) | < 0.01 | 128 (47.2) | 128 (47.2) | 1.00 |
> 0.1 | 237 (30.3) | 217 (59.6) | 143 (52.8) | 143 (52.8) | ||
Yes | 584 (96.1) | 257 (90.5) | < 0.01 | 197 (94.7) | 187 (90.7) | 0.12 |
No | 24 (3.9) | 27 (9.5) | 11 (5.3) | 19 (9.3) | ||
Yes | 34 (29.1) | 11 (15.9) | 0.04 | 17 (34.0) | 11 (20.0) | 0.11 |
No | 83 (70.9) | 58 (84.1) | 33 (66.0) | 44 (80.0) |
Values are presented as number (%). WBI, whole-breast irradiation; SCNRT, supraclavicular radiotherapy; IDC, invasive ductal carcinoma; LVI, lymphovascular invasion; HG, histologic grade; HER-2, human epidermal growth factor receptor-2; LN, lymph node.
Ratio of positive LNs to total dissected LNs,
Endocrine therapy was administered to patients with hormone-responsive tumors, such as luminal A, luminal B, and luminal HER2. The value in parentheses represents the proportion of patients with hormone-responsive tumor,
The value in parentheses represents the proportion of patients with HER2-amplified tumor.
Patterns of the first failure according to field of radiotherapy
Sites of the first failure | WBI alone (n=271) | WBI+SCNRT (n=271) | p-value |
---|---|---|---|
3 (1.1) | 6 (2.2) | 0.47 | |
Local only | 2 (0.7) | 3 (1.1) | |
Regional only |
1 (0.4) | 3 (1.1) | |
13 (4.8) | 10 (3.7) | ||
5 (1.9) | 4 (1.5) | ||
Regional and distant | 4 (1.5) | 4 (1.5) | |
Loco-regional and distant | 1 (0.4) | 0 (0.0) | |
21 (7.7) | 20 (7.4) |
Values are presented as number (%). WBI, whole-breast irradiation; SCNRT, supraclavicular radiotherapy.
Regional recurrence occurred in the axillary lymph node (n=1) in WBI alone and the internal mammary lymph node (n=3) in WBI+SCNRT. Supraclavicular lymph node failure was detected in three patients, two in WBI alone and one in WBI+SCNRT. All supraclavicular lymph node failures were found simultaneously with distant metastasis.
DFS according to patient and tumor characteristics between WBI alone and WBI+SCNRT
Characteristic | 5-Yr DFS (%) |
HR (95% CI) | ||
---|---|---|---|---|
WBI alone | WBI+SCNRT | p-value |
||
≤ 40 | 93.6 | 88.3 | 0.27 | 1.52 (0.45-5.21) |
> 40 | 94.5 | 94.3 | 1.13 (0.53-2.41) | |
≤ 20 | 96.0 | 96.1 | 0.15 | 1.03 (0.31-3.31) |
> 20 | 92.9 | 89.9 | 1.34 (0.63-2.89) | |
Single | 94.1 | 92.4 | 0.46 | 1.29 (0.67-2.49) |
Multiple | 95.6 | 97.5 | 0.62 (0.04-6.01) | |
Negative | 96.2 | 97.1 | 0.09 | 0.32 (0.04-2.96) |
Positive | 93.6 | 91.5 | 1.45 (0.73-2.85) | |
1, 2 | 96.1 | 96.3 | 0.06 | 0.79 (0.28-2.23) |
3 | 91.9 | 88.7 | 1.64 (0.71-3.78) | |
Luminal A | 97.0 | 96.2 | 0.17 | 0.98 (0.31-3.06) |
Non-luminal A | 91.7 | 90.5 | 1.31 (0.59-2.83) | |
1, 2 | 95.2 | 93.5 | 0.64 | 1.51 (0.71-3.19) |
3 | 91.5 | 91.9 | 0.71 (0.20-2.51) | |
≤ 0.1 | 96.8 | 95.4 | 0.06 | 1.29 (0.36-4.69) |
> 0.1 | 92.2 | 91.4 | 1.14 (0.55-2.38) |
DFS, disease-free survival; WBI, whole-breast irradiation; WBI+SCNRT, WBI with supraclavicular lymph node radiotherapy; HR, hazard ratio; CI, confidence interval; LVI, lymphovascular invasion; HG, histologic grade; LN, lymph node.
The logrank test was used to compare survival between groups,
Ratio of positive LNs to total dissected LNs.
Treatment-related toxicities
Morbidity | WBI alone (n=271) |
WBI+SCNRT (n=271) |
p-value |
||||
---|---|---|---|---|---|---|---|
Grade 1 | Grade 2 | Total | Grade 1 | Grade 2 | Total | ||
Lymphedema | 23 (8.5) | 6 (2.2) | 29 (10.7) | 33 (12.2) | 12 (4.4) | 45 (16.6) | 0.04 |
Pneumonitis | 2 (0.7) | 0 | 2 (0.7) | 11 (4.1) | 0 | 11 (4.1) | 0.01 |
Values are presented as number (%). WBI, whole-breast irradiation; SCNRT, supraclavicular radiotherapy.
p-values were calculated by Fisher exact test to compare the proportion of patients with complication of grade 1 or higher between groups.
Studies reporting the incidence of SCN metastasis after whole-breast radiotherapy with or without elective SCN irradiation in patients with N1 breast cancer
Study | Design | Years of accrual | No. of N1 patients | HTx (%) | CTx (%) | CTx agents | RT field | SCN failure (total/isolated) | Survival |
---|---|---|---|---|---|---|---|---|---|
Livi et al. [ |
Retrospective | 1980-2001 | 823 | 36 |
21.8 |
Anthracycline-based (20%), CMF (65%), others (15%) | WBI | 0.9%/NR | NR |
Reddy et al. [ |
Retrospective | 1985-2002 | 202 | 66 | 72 | Anthracycline-based (57%), others (15%) | WBI | 2.0%/0.5% | SCNFFS: 97.9%, at 5 yr |
Truong et al. [ |
Retrospective | 1989-1999 | 1,255 | 64 |
59.6 |
NR | WBI (n=817) | 2.2%/NR | LRRFS: 88.8% (WBI), 92.5% (WBI+SCNRT), at 10 yr |
WBI+SCNRT (n=438) | |||||||||
Yu et al. [ |
Retrospective | 1999-2003 | 448 | 61 | 98.9 | CMF (63%), AC (28%), FAC (8%) | WBI | 8.7%/1.8% | DMFS: 85.7%, SCNFFS: 92.6% at 5 yr |
Yates et al. [ |
Retrospective | 1975-2000 | 1,065 | 6-79 |
24-49 |
CMF (74%), melphalan (17%), anthracycline (7%) | WBI | 9.2%/NR | SCNFFS: 93.0%, at 5 yr |
Whelan et al. [ |
Prospective, randomized | 2000-2007 | 1,558 | 75.4 |
90.5 |
Anthracycline (86%), AT (26%) | WBI (n=780) | NR | DFS: 87.0% vs. 92.4% |
WBI+RNI (n=778) | DMFS: 87.0% vs. 92.4%, at 5 yr | ||||||||
Poortmans et al. |
Prospective, randomized | 1996-2004 | 1,725 | 59.6 |
54.7 |
NR | WBI or CWI (n=780) | NR | DFS: 69.1% vs. 79.1% |
WBI or CWI+RNI (n=778) | DMFS: 75.0% vs. 78.0%, at 10 yr | ||||||||
Current study | Retrospective, case-control | 2006-2010 | 542 | 92.8 | 100 | AT (100%) | WBI (n=271) | 0.7%/0.0% | DFS: 94.4% vs. 92.6% |
WBI+SCNRT (n=271) | 0.4%/0.0% | DMFS: 95.1% vs. 94.5%, at 5 yr |
SCN, supraclavicular lymph node; HTx, hormone therapy; CTx, chemotherapy; RT, radiotherapy; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; WBI, whole-breast irradiation; NR, not reported; SCNFFS, supraclavicular lymph node failure-free survival; SCNRT, supraclavicular radiotherapy; LRRFS, loco-regional recurrence-free survival; AC, adriamycin and cyclophosphamide; FAC, 5-fluorouracil, adriamycin, and cyclophosphamide; DMFS, distant metastasis failure-free survival; AT, anthracycline with taxane; RNI, regional-nodal irradiation (internal mammary, supraclavicular, and axillary lymph nodes); DFS, disease free survival; CWI, chest wall irradiation.
The study included 4,185 patients with N0 (68.6%), N1 (19.7%), N2 (9.3%), or unknown nodal status (2.4%) breast cancer. The proportions indicate the number of patients who underwent hormone therapy or chemotherapy among all patients,
There were 469 patients (37%) treated with hormone therapy alone, 408 patients (33%) treated with chemotherapy alone, and 340 patients (27%) treated with both hormone therapy and chemotherapy,
The proportion of patients receiving hormone therapy and chemotherapy increased with time. The rate of SCN failure steadily decreased over the same time period,
Proportion of patients receiving hormone therapy or chemotherapy relative to all patients with N0-N2 breast cancer. Survival was not specified solely for N1 cases,
The study included patients with N0-N3 breast cancer treated with breast-conserving surgery (76.1%) or mastectomy (23.9%). The proportion of patients treated with hormone therapy or chemotherapy was calculated among patients with N0-N3 disease. Survival was not specified solely for N1 cases.