Patients With T1 to T2 Breast Cancer With One to Three Positive Nodes Have Higher Local and Regional Recurrence Risks Compared With Node-Negative Patients After Breast-Conserving Surgery and Whole-Breast Radiotherapy

Int. J. Radiation Oncology Biol. Phys., Vol. 73, No. 2, pp. 357–364, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2008.04.034

CLINICAL INVESTIGATION

Breast

PATIENTS WITH T1 TO T2 BREAST CANCER WITH ONE TO THREE POSITIVE NODES HAVE HIGHER LOCAL AND REGIONAL RECURRENCE RISKS COMPARED WITH NODE-NEGATIVE PATIENTS AFTER BREAST-CONSERVING SURGERY AND WHOLEBREAST RADIOTHERAPY PAULINE T. TRUONG, M.D., C.M., F.R.C.P.C.,*y STUART O. JONES, B.SC.,* HOSAM A. KADER, M.D., F.R.C.P.C.,* ELAINE S. WAI, M.D., F.R.C.P.C.,*y CAROLINE H. SPEERS, B.A.,y ABRAHAM S. ALEXANDER, M.D., F.R.C.P.C.,* AND IVO A. OLIVOTTO, M.D., F.R.C.P.C.*y * Radiation Therapy Program and y Breast Cancer Outcomes Unit, British Columbia Cancer Agency, Vancouver Island Centre, University of British Columbia, Victoria, BC, Canada Purpose: To evaluate locoregional recurrence according to nodal status in women with T1 to T2 breast cancer and zero to three positive nodes (0–3N+) treated with breast-conserving surgery (BCS). Methods and Materials: The study subjects comprised 5,688 women referred to the British Columbia Cancer Agency between 1989 and 1999 with pT1 to T2, 0–3N+, M0 breast cancer, who underwent breast-conserving surgery with clear margins and radiotherapy (RT) of the whole breast. The 10-year Kaplan-Meier local, regional, and locoregional recurrence (LR, RR, and LRR, respectively) were compared between the N0 (n = 4,433) and 1–3N+ (n = 1,255) cohorts. The LRR was also examined in patients with one to three positive nodes (1–3N+) treated with and without nodal RT. Multivariate analysis was performed using Cox regression modeling. Results: Median follow-up was 8.6 years. Systemic therapy was used in 97% of 1–3N+ and 41% of N0 patients. Nodal RT was used in 35% of 1–3N+ patients. The 10-year recurrence rates in N0 and 1–3N+ cohorts were as follows: LR 5.1% vs. 5.8% (p = 0.04); RR 2.3% vs. 6.1% (p < 0.001), and LRR 6.7% vs. 10.1% (p < 0.001). Among 817 1–3N+ patients treated without nodal RT, 10-year LRR were 13.8% with age <50 years, 20.3% with Grade III, and 23.4% with estrogen receptor (ER)–negative disease. On multivariate analysis, 1–3N+ status was associated with significantly higher LRR (hazard ratio [HR], 1.85; 95% confidence interval, 1.34–2.55, p < 0.001), whereas nodal RT significantly reduced LRR (HR, 0.59; 95% confidence interval, 0.38–0.92, p = 0.02). Conclusion: Patients with 1–3N+ and young age, Grade III, or ER-negative disease have high LRR risks approximating 15% to 20% despite BCS, whole-breast RT and systemic therapy. These patients may benefit with more comprehensive RT volume encompassing the regional nodes. Ó 2009 Elsevier Inc. Breast cancer, Node-positive, Node-negative, Locoregional recurrence, Breast radiotherapy, Regional nodal radiotherapy.

INTRODUCTION In patients with Stage I to II breast cancer, breast-conserving surgery (BCS) followed by adjuvant radiotherapy (RT) provides equivalent local control and survival compared with mastectomy (1–4). Although there is consensus that RT to the whole breast is standard care after BCS for early stage breast cancer, the role of adjuvant RT to the regional nodes in women with T1 to T2 breast cancer and one to three positive nodes (1–3N+) is controversial. In a survey of North American and European radiation oncologists’ self-reported management of breast cancer, Ceilley et al. identified significant national and international variations in clinicians’ opinion

regarding what they consider to be appropriate management of the regional nodes after mastectomy and after BCS (5). Similar to the postmastectomy setting (6–8), much of the controversy regarding adjuvant management of patients with small volume nodal involvement treated with BCS is caused by divergent opinions regarding their baseline risks of local and regional recurrence after definitive breast surgery and nodal staging. The current report is an analysis of breast and regional nodal recurrence in women with T1 to T2 breast cancer and zero to three positive nodes treated with BCS. The study aims to evaluate locoregional recurrence outcomes in patients with one to three positive nodes compared with

Reprint requests to: Pauline T. Truong, M.D., C.M., BC Cancer Agency, Vancouver Island Centre, 2410 Lee Avenue, Victoria, BC, Canada, V8R 6V5. Tel: (250) 519-5575; Fax: (250) 5192018; E-mail: [email protected] Presented in part at the 49th Annual American Society of

Therapeutic Radiology Oncology Meeting, Oct 28–Nov 1, 2007, Los Angeles, CA. Conflict of interest: none. Received Feb 3, 2008, and in revised form April 10, 2008. Accepted for publication April 11, 2008. 357

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node-negative disease, and to identify adverse prognostic factors associated with high locoregional recurrence risks that may be used in making decisions about the use of adjuvant RT. METHODS AND MATERIALS Study subjects The British Columbia Cancer Agency (BCCA) Breast Cancer Outcomes Unit database was used to identify 5,688 BC resident women with breast cancer diagnosed between January 1, 1989, and December 31, 1999. All women had been referred with newly diagnosed invasive breast cancer, pT1 to pT2, zero to three positive nodes, M0, treated with BCS with clear surgical margins and axillary staging, followed by adjuvant breast RT. The analysis excluded patients treated with mastectomy, patients who did not undergo RT after BCS, patients with unknown nodal status, and patients with previous or synchronous breast cancer. Two cohorts were analyzed: those with no positive nodes, designated as having N0 disease (n = 4,433) and those designated as having 1–3N+ disease (n = 1,255).

Locoregional and systemic therapy All patients underwent BCS and axillary dissection. The median number of nodes removed was 10 (range, 1–50). In all, 85% of N0 patients and 88% of 1–3N+ patients had a minimum of six nodes removed. During the study era, the British Columbia Cancer Agency guidelines recommended RT to the whole breast for all patients with invasive breast cancer treated with BCS. RT to the regional nodes, was recommended for patients with 1–3N+ disease with bulky nodes, including nodal metastases greater than 2 cm, or the presence of extranodal extension (9). Decisions regarding RT volume were individualized by the treating radiation oncologist and generally included the axillary and supraclavicular nodes. The internal mammary nodes were not routinely treated. All patients underwent adjuvant whole-breast RT, using tangential beams delivering 40 to 50 Gy in 15 to 25 daily fractions with Cobalt-60 or 4 to 18 MV photons. In 35% (n = 438) of 1–3N+ patients and 0.5% (n = 20) of N0 patients, RT to the breast plus regional nodes was used. Systemic therapy was used in 97% (n = 1217) of 1–3N+ patients and 41% (n = 1835) of N0 patients.

Outcomes and variables analyzed The primary outcomes examined were: local recurrence (LR), defined as the first site of tumor recurrence involving the ipsilateral breast; regional recurrence (RR), defined as the first site of tumor recurrence involving the axillary, supraclavicular, infraclavicular, or internal mammary nodes; and locoregional recurrence (LRR), defined as the first site of tumor recurrence involving the ipsilateral breast and/or regional nodes. LRR occurring more than 1 month after a distant recurrence event were censored. The tumor factors analyzed were as follows: histology (ductal, lobular, other); T stage (T1, T2); histologic grade (Grade I, II, III, unknown); lymphovascular invasion (LVI) (positive, negative, unknown); and estrogen receptor (ER) status (positive, negative, unknown). Nodal factors analyzed were the number of positive nodes (none, one, two, three) and the percentage of positive nodes (#20%, >20%). Selection of the 20% positive nodes cutoff was based on published reports demonstrating its prognostic significance in predicting LRR risks for women with 1–3N+ disease treated with mastectomy (10, 11). Adjuvant systemic therapy use was classified on a yes-or-no basis. The type of systemic therapy used was classified as hormone therapy alone, chemotherapy alone, both, or none.

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Statistical analysis Comparisons of tumor and treatment characteristics between patients with N0 and 1–3N+ breast cancer were performed using Chisquare and Fisher’s exact tests. The 10-year estimates of LR, RR, and LRR were computed using Kaplan-Meier methods and compared between the N0 and 1–3N+ cohorts using the log-rank test. Locoregional recurrence in the 1–3N+ cohort was further examined according to treatment with or without nodal RT. The 10-year KM LR, RR, and LRR were computed for patient and tumor factors for patients with 1–3N+ treated without nodal RT to identify possible predictors of high LRR risk. Multivariate analysis was performed using Cox proportional hazards regression modeling. All analyses were conducted using SPSS software version 14.0.2 (SPSS Inc., Chicago, IL). The study was approved by the University of British Columbia research ethics board.

RESULTS Clinicopathologic characteristics The median follow-up time was 8.6 years (range, 0.25– 16.5 years). Table 1 summarizes data on the clinicopathologic characteristics of the entire cohort and comparisons between N0 and 1–3N+ patients. Compared with N0 patients, patients with 1–3N+ had higher proportions of age <50 years, T2 disease, Grade III histology, and lymphovascular invasion (all p < 0.001). Distributions of histologic subtypes and ER status were similar in the two cohorts. Local and regional recurrence outcomes Crude rates and 10-year Kaplan-Meier LR, RR, and LRR rates in N0 and 1–3N+ patients are summarized in Table 2. The 10-year KM recurrence rates were higher in 1–3N+ compared with N0 patients: LR 5.8% vs. 5.1%, (p = 0.04); RR 6.1% vs. 2.3%, (p < 0.001); and LRR 10.1% vs. 6.7% (p < 0.001) (Fig. 1). In the entire cohort, 155 (2.7%) patients experienced regional recurrence. Regional recurrence occurred in 2.0% of N0 patients and in 5.4% of 1–3N+ patients. The most common site of regional recurrence was the axilla, followed by the supra- or infraclavicular nodes (Table 3). The median number of nodes removed among patients who experienced an axillary recurrence was eight. Recurrence involving the internal mammary nodes was 0.1%. Figure 2 depicts the comparison of LRR in patients with 1– 3N+ treated with nodal RT (n = 438) and without nodal RT (n = 817). The 10-year KM LRR was 11.2% without nodal RT and 7.5% with nodal RT (p = 0.06). Table 4 presents comparisons of the 10-year KM LR, RR, and LRR rates stratified by clinicopathologic characteristics in 817 patients with 1–3N+ treated without nodal RT. Age less than 50 years, Grade III histology, and ER negative status were factors significantly associated with higher 10-year KM LR, RR, and LRR. The magnitude of 10-year LRR with these characteristics were: 13.8% with age less than 50 years vs. 9.6% with age 50 years or more (p = 0.02), 20.3% with Grade III vs. 6.2% with Grade I/II, (p < 0.001), and 23.4% with ERnegative disease vs. 8.3% with ER-positive disease (Figure 3). The presence of more than one positive node or more than

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Table 1. Clinicopathologic characteristics in the entire cohort and comparisons between patients with node-negative (N0) and one-to-three nodes positive (1–3N+) disease Characteristic Age (y) Median (range) <50 $50 Histology Ductal Lobular Other T stage T1 T2 Grade I II III Unknown Lymphovascular invasion Negative Positive Unknown Estrogen receptor status Positive Negative Unknown No. of excised nodes Median (range) #5 6–10 11–15 $16 Unknown Nodal radiotherapy Systemic therapy Hormone therapy alone Chemotherapy alone Both None

Entire cohort (n = 5,688)

N0 (n = 4,433)

1–3N + (n = 1,255)

57 (21–88) 1,710 (30) 3,978 (70)

58 (21–87) 1,228 (28) 3,205 (72)

5,269 (93) 337 (6) 82 (1)

4,088 (92) 278 (6) 67 (2)

1,181 (94) 59 (5) 15 (1)

4,380 (77) 1,308 (23)

3,576 (81) 857 (19)

804 (64) 451 (36)

1,052 (19) 2,642 (46) 1,778 (31) 216 (4)

913 (21) 2,065 (47) 1,282 (29) 173 (4)

139 (11) 577 (46) 496 (40) 43 (3)

4,255 (75) 1,252 (22) 181 (3)

3,619 (82) 687 (15) 127 (3)

636 (51) 565 (45) 54 (4)

3,875 (68) 1,163 (20) 650 (11)

2,989 (67) 887 (20) 557 (13)

886 (71) 276 (22) 93 (7)

10 (1–50) 774 (14) 2,247 (40) 1,665 (29) 959 (17) 43 (1) 458 (8) 3,052 (54) 1,532 (27) 968 (17) 552 (10) 2,636 (46)

10 (1–50) 624 (14) 1,768 (40) 1,281 (29) 720 (16) 40 (1) 20 (0.5) 1,835 (41) 1,063 (24) 560 (13) 212 (5) 2,598 (59)

54 (24–88) 482 (38) 773 (62)

p*

<0.001 0.08

<0.001 <0.001

<0.001

0.55

10 (1–35) 150 (12) 479 (38) 384 (31) 239 (19) 3 (0) 438 (35.0) 1,217 (97) 469 (37) 408 (33) 340 (27) 38 (3)

0.02

<0.001 <0.001

Data presented as number (%) unless otherwise specified. * Test statistics applied to known values only.

20% positive nodes was associated with significantly higher regional, but not local, recurrence risk (Table 4). Multivariate analysis Table 5 presents the Cox regression analysis of patient, tumor, and treatment variables on LRR after BCS. Nodepositive status was associated with significantly increased LRR (hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.34–2.55, p < 0.001). Other significant predictors of

LRR were age, grade, LVI, and percent positive nodes. The LRR was reduced with the use of nodal RT (HR, 0.59; 95% CI, 0.38–0.92, p = 0.02) and systemic therapy (HR, 0.59; 95% CI, 0.44–0.80; p = 0.001).

DISCUSSION The goal of adjuvant locoregional management for women with early stage breast cancer is to provide optimal local and

Table 2. Crude rates and 10-year Kaplan-Meier (KM) rates of local, regional, and locoregional recurrence in patients with node-negative (N0) and one-to-three nodes positive (1–3N+) disease N0 (n = 4,433)

1–3N+ (n = 1,255)

Recurrence

Crude rate N (%)

10-year KM rate (%)

Crude rate N (%)

10-year KM rate (%)

Log-rank p

Local Regional Locoregional

187 (4.2) 87 (2.0) 247 (5.6)

5.1 2.3 6.7

67 (5.3) 68 (5.4) 117 (9.3)

5.8 6.1 10.1

0.04 <0.001 <0.001

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Fig. 1. Comparison of (a) local recurrence (b) regional recurrence and (c) locoregional recurrence in node-negative (N0) and 1-3 positive nodes (1–3N+) patients

regional control with acceptable normal tissue toxicities and cosmesis. Improved locoregional control can also reduce breast cancer mortality (2, 12). The current study has demonstrated that patients with 1–3N+ have substantially higher risks of locoregional recurrence after BCS compared with N0 counterparts. Patients with 1–3N+, in combination with age less than 50 years, high-grade tumors, or ER-negative disease, have LRR risks approximating 15% to 20% despite Table 3. Sites of regional recurrence in patients with nodenegative (N0) and one-to-three nodes positive (1–3N+) breast cancer Regional recurrence

Entire cohort (n = 5,688)

N0 (n = 4,433)

1–3N+ (n = 1,255)

Total Axillary nodes Supra-/infraclavicular nodes Internal mammary nodes >1 Regional nodal site

155 (2.7) 90 (1.6) 59 (1.0)

87 (2.0) 50 (1.1) 32 (0.7)

68 (5.4) 40 (3.2) 27 (2.2)

5 (0.1)

4 (0.1)

1 (0.1)

1 (0.02)

1 (0.02)

0 (0)

Data are presented as number (%).

BCS with clear margins, axillary dissection, and adjuvant whole-breast radiotherapy (WBRT) and systemic therapy. In contemporary practice with increased use of BCS and adjuvant systemic therapy, optimal adjuvant locoregional management for women with T1 to T2 breast cancer and 1–3N+ after BCS is controversial. In the current study, only patients who received standard WBRT after BCS were selected for analysis. We focussed on the risk of regional recurrence beyond the breast in patients with 1–3N+ treated with BCS therapy without nodal RT. Our series documented a regional recurrence rate of 2.7% in patients with 0–3N+, consistent with other studies reporting regional recurrence outcomes after BCS (13–18). This rate can be attributed to axillary dissection removing a median of 10 nodes and to the fact that N0 patients comprised 80% of the 0–3N+ cohort. When N0 and 1–3N+ patients were compared as separate groups, however, the 5.4% regional recurrence rate in patients with 1–3N+ was more than twice the rate in N0 patients. In 1–3N+ patients treated without nodal RT, subsets with young age, Grade III disease and ER-negative tumors experienced regional recurrence rates approximating 10% to 15% and LRR rates approximating 15% to 20%. The magnitude of these

Recurrence risk in T1 to T2 breast cancer patients d P. T. TRUONG et al.

Fig. 2. Locoregional recurrence in 1–3N+ patients treated with versus without nodal radiotherapy

risks supports the contentions that not all patients with 1–3N+ disease have low regional recurrence risk, and that it is possible to identify higher-risk subsets of patients in whom locoregional control may be improved with more comprehensive RT volume.

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Variations in surgical practice can affect LRR risks. In the current report, all patients had clear surgical margins after BCS and axillary dissection removing a median of 10 nodes. In the postmastectomy setting, discrepancies in the reported baseline LRR risks in patients with 1–3N+ have been attributed to variations in the extent of axillary surgery yielding different numbers of excised nodes (6–8). In node-positive patients treated with mastectomy, the percentage of positive/excised nodes has been reported to be a significant prognostic indicator for LRR (10, 11). Investigators from British Columbia and the MD Anderson Cancer Center reported an analysis of 82 patients with 1–3N+ treated without RT on the British Columbia postmastectomy randomized trial compared with 462 patients with 1–3N+ treated without RT in prospective chemotherapy trials at the MD Anderson Cancer Center (11). In that study, the presence of >20% positive nodes was associated with LRR risks in excess of 20%, and the multivariate analysis found the percentage of positive nodes to be a stronger prognostic factor for LRR compared with absolute number of positive nodes (19). In the BCS setting, an analysis by Fortin et al. of 1,372 women with T1 to T2, node-positive breast cancer treated with BCS also identified the percentage of positive nodes to be significantly associated with LRR. In that series, regional RT after BCS improved axillary control for patients with 1–3N+ and less than 40% positive nodes (19). The current study similarly confirmed

Table 4. Ten-year Kaplan-Meier (KM) local, regional, and locoregional recurrence according to clinicopathologic factors in 817 patients with T1 to T2 breast cancer and one-to-three nodes positive (1–3N+) disease treated without nodal radiotherapy Characteristic Age (y) <50 $50 Histology Lobular Ductal T stage T1 T2 Grade I/II III LVI Positive Negative ER status Positive Negative No. of positive nodes 1 2 3 No. of excised nodes <10 $10 % Positive nodes #20% >20%

10-year KM local recurrence (%)

p

10-year KM regional recurrence (%)

0.01 7.8 4.7 0.12

0.16

0.001

<0.001

0.46

0.71

<0.001

<0.001

0.91

<0.001 8.3 23.4

0.02 5.5 10.6 11.2

0.77 5.6 6.0

0.18 12.7 10.4

5.2 14.9

6.5 4.4 4.2

<0.001 6.2 20.3

7.7 6.9

4.3 13.4

0.36 9.9 14.3

3.1 14.3

6.2 5.9

0.03 0.0 11.3

6.0 10.1

3.6 9.6

0.02

0.10

0.64

0.07 10.3 12.6 15.1

0.10 9.4 5.7

0.62

0.56 12.2 10.5

0.03 6.2 11.2

Abbreviations: ER = estrogen receptor; LVI = lymphovascular invasion.

p

13.8 9.6

0.0 7.2

5.9 5.8

10-year KM locoregional recurrence (%)

0.03 10.0 5.5

0.0 5.9

6.0 5.0

p

0.26 10.7 13.1

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Table 5. Multivariate Cox regression analysis of locoregional recurrence Locoregional recurrence Variable Age (y) (<50 vs. $50) Histology (lobular vs. ductal) T stage (T2 vs. T1) Nodal status (1–3N+ vs. N0) % Positive nodes (>20% vs. #20%) Grade (III vs. I/II) LVI status (positive vs. negative) ER status (negative vs. positive) Nodal RT (yes vs. no) Systemic therapy (yes vs. no)

Hazard ratio (95% confidence interval)

p

1.58 (1.25–2.0) 0.83 (0.45–1.52) 1.31 (1.00–1.70) 1.85 (1.34–2.55) 1.64 (1.01–2.49)

<0.001 0.54 0.05 <0.001 0.02

1.96 (1.51–2.53) 1.54 (1.17–2.02) 1.29 (0.99–1.69) 0.59 (0.38–0.92) 0.59 (0.44–0.80)

<0.001 0.002 0.06 0.02 0.001

Abbreviations: ER = estrogen receptor; LVI = lymphovascular invasion.

Fig. 3. Locoregional recurrence in 1–3N+ patients treated without nodal radiotherapy stratified by (a) age, (b) ER status, and (c) grade.

the prognostic significance of the percentage of positive nodes in the breast conservation setting and supports the suggestion that the absolute number and the percentage of positive nodes be jointly considered in the appraisal of post-BCS regional recurrence risk for patients with 1–3N+ disease.

In modern practice, sentinel node biopsy has emerged as an accurate staging modality with less surgical morbidity compared with axillary dissection (20). Its role as a standalone procedure without axillary dissection is being investigated by prospective randomized trials (21). Because sentinel node surgery generally yields fewer nodes compared with axillary dissection, the long-term locoregional control and survival associated with this procedure relative to axillary dissection remain to be established. The identification of 1– 3N+ subsets with high LRR risks despite being considered to have small-volume nodal disease in this analysis supports current practice standards of completion axillary dissection in the presence of positive sentinel nodes. Although surgery and RT are the principal locoregional treatments for breast cancer, systemic therapy also has the potential to favorably impact locoregional control in patients with early stage breast cancer. The Early Breast Cancer Trialists’ Collaboration Group meta-analysis of systemic therapy trials demonstrated that chemotherapy reduced LR by approximately one-third and that 5 years of tamoxifen reduced the LR rate by about one half in women with ER-positive breast cancer (22). The current analysis identified ER-negative disease to be associated with higher LRR, likely because patients with ER-negative tumors were less likely to receive hormone therapy. Our multivariate analysis showed that systemic therapy and nodal RT both exerted favorable effects on LRR. This finding is consistent with the Early Breast Cancer Trialists’ Collaboration Group overview’s demonstration that local treatments which produced more than a 10% absolute reduction in 5-year local recurrence were effective in the presence or absence of systemic therapy, highlighting the principle that better local treatment adds to the effects of systemic therapy on improving long-term locoregional disease control (22). The association between age 50 years or less and higher LRR risk despite standard BCS and systemic therapy

Recurrence risk in T1 to T2 breast cancer patients d P. T. TRUONG et al.

demonstrated in the current series corroborate other series reporting young age to be an adverse prognostic factor for higher LRR compared with older counterparts (13, 15, 17, 23). In addition to young age, Grade III histology and LVI were other clinical factors identified in the current study’s multivariate analysis to be significant risk factors for LRR after BCS. Efforts to improve locoregional control in patients with these adverse features are warranted, because local and regional recurrence have been shown to confer increased risks of distant metastasis and breast cancer mortality (17, 23–25). In an analysis of 2,669 women enrolled in five randomized National Surgical Adjuvant Breast and Bowel Project node-positive protocols that were treated with BCS, WBRT, and adjuvant systemic therapy, age, tumor size, and ER status were significantly associated with in-breast recurrence. Nodal involvement and ER-negative status were significant predictors for other LRR events. In node-positive patients, breast recurrence and other locoregional recurrences were associated with a mortality HR of 2.58 and 5.85, respectively (23). The opportunity to improve survival by optimizing locoregional control continues to provide the impetus to better define selection criteria for adjuvant RT and individualize management decisions. Although the current study is limited by its retrospective design with inherent biases in patient and treatment selection, including RT decisions, it has potential value in providing long-term outcomes information in a large, geographically defined patient population managed with provincial treatment guidelines the outcomes of which have been demonstrated to be representative of other breast cancer populations (26). It is interesting to note that regional recurrence in patients with 1–3N+ disease occurred mainly in the axilla and supraclavicular nodes and that internal mammary nodal recurrence was very rare. These data help to confirm the approach of clinicians administering RT to the upper axilla and supraclavicular nodes, but not the internal mammary nodes, in patients with one to three positive nodes. Ultimately, however, for patients with 1–3N+ disease treated with BCS, the question of what constitutes optimal adjuvant RT volume will be best answered by well-designed prospective trials taking into account not only local but also regional recurrence as

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study endpoints. The National Cancer Institute of Canada (NCIC) MA20 trial randomized node-positive and highrisk node-negative patients after BCS to RT to the breast vs. RT to the breast plus regional nodes (27). This trial recently completed accrual but will require years of followup before conclusive findings can be generated. Distinct from the NCIC MA20 trial which examined more, rather than less, comprehensive RT volume after BCS, other trials are underway to evaluate the role of partial-breast RT directed only to the primary tumor bed as adjuvant local management for early-stage breast cancer. The two ongoing multi-institutional randomized trials in North America comparing partial-breast RT with standard whole-breast RT have divergent eligibility criteria with respect to nodal status. In the Canadian Randomized Trial of Accelerated Partial Breast Irradiation (RAPID), enrollment is restricted to patients with pathologic N0 disease. In the National Surgical Adjuvant Breast and Bowel Project B39/Radiation Therapy Oncology Group 0413 trial, patients with 1–3N+ disease are also eligible. Acknowledging that divergent opinions and debates regarding risk magnitudes and management philosophy for patients with 1–3N+ disease will continue in the breast radiation oncology community, the current report documenting increased locoregional recurrence even with small volume nodal involvement raises the concern that such patients may have higher future risks of inferior long-term locoregional control and possibly survival on a trial in which the experimental intervention is restricted to only the primary tumor bed.

CONCLUSION Patients with T1 to T2 breast cancer and 1–3N+ disease are at higher risk for locoregional recurrence compared with node-negative patients after BCS and axillary dissection. Patients with 1–3N+ disease with younger age (#50 years), Grade III disease, or ER-negative disease have locoregional recurrence risks approximating 15% to 20% despite WBRT and systemic therapy. These patients may benefit with more, rather than less, comprehensive locoregional RT volume.

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18. Pejavar S, Wilson LD, Haffty BG. Regional nodal recurrence in breast cancer patients treated with conservative surgery and radiation therapy (BCS+RT). Int J Radiat Oncol Biol Phys 2006; 66:1320–1327. 19. Fortin A, Dagnault A, Blondeau L, et al. The impact of the number of excised axillary nodes and of the percentage of involved nodes on regional nodal failure in patients treated by breast-conserving surgery with or without regional irradiation. Int J Radiat Oncol Biol Phys 2006;65:33–39. 20. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349:546–553. 21. White RL Jr., Wilke LG. Update on the NSABP and ACOSOG breast cancer sentinel node trials. Am Surg 2004;70:420–424. 22. Early Breast Cancer Trialists’ Collaboration Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;365:1687–1717. 23. Wapnir IL, Anderson SJ, Mamounas EP, et al. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrence in five National Surgical Adjuvant Breast and Bowel Project node-positive adjuvant breast cancer trials. J Clin Oncol 2006;24:2028–2037. 24. Whelan T, Clark R, Roberts R, et al. Ipsilateral breast tumor recurrence postlumpectomy is predictive of subsequent mortality: Results from a randomized trial. Investigators of the Ontario Clinical Oncology Group. Int J Radiat Oncol Biol Phys 1994; 30:11–16. 25. Fortin A, Larochelle M, Laverdiere J, et al. Local failure is responsible for the decrease in survival for patients with breast cancer treated with conservative surgery and postoperative radiotherapy. J Clin Oncol 1999;17:101–109. 26. Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model Adjuvant! for early breast cancer. J Clin Oncol 2005;23:2716–2725. 27. Olivotto IA, Chua B, Elliott EA, et al. A clinical trial of breast radiation therapy versus breast plus regional radiation therapy in early-stage breast cancer: The MA20 trial. Clin Breast Cancer 2003;4:361–363.