1、© 2012 Korean Breast Cancer Society. All rights reserved.http:/ejbc.kr | pISSN 1738-6756eISSN 2092-9900This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (/licenses/by-nc/3.0 which permits unrestricted n

2、on-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.INTRODUCTIONAdjuvant radiation therapy (RT improved locoregional control and overall survival in breast cancer patients treated with upfront surgery, as shown in three randomized trials and

3、one meta-analysis 1-4. These studies, which routinely included the supraclavicular lymph node (SCN region in the radiation field of adjuvant RT group, showed that adjuvant RT reduced the locoregional recurrence (LRR in pathological N1 and N2 (pN1-N2 patients. In contrast, several studies reported SC

4、N recurrence rates as low as 1% to 8% when supraclavicular radiation therapy (SCNRT was not used in pN0-N1 patients 5-8. These conflicting findings have resulted in considerabledebate regarding the use of SCNRT for pN1 breast cancer patients. Recently, prognostic factors associated with SCN recurren

5、ce were identified that might help in the selection of patients who will benefit from SCNRT 9,10.In locally advanced breast cancer patients, neoadjuvant chemotherapy (NAC followed by surgery showed similar failure rate and survival rate compared to surgery followed by chemotherapy 11-13. Although NA

6、C followed by surgery for locally advance breast cancer patients is increased, the indication for adjuvant RT and the optimal radiation field of the regional lymphatics are unclear because approximately 80% to 90% of patients had changes in the pathological extent of tumor compared to clinical tumor

7、 extent 11,14,15. Patients who presented with clinically advanced stage III or IV disease but who subsequently achieved a pathologic complete response (pCR to NAC still had a high rate of LRR, suggesting that RT should be considered. The National Comprehensive Cancer Network (NCCN guidelines recomme

8、nd indication for RT and fields of treatment should be based upon the pretreat-ment tumor characteristics in patients treated with NAC 16.Radiation Treatment in Pathologic N0-N1 Patients Treated with Neoadjuvant Chemotherapy Followed by Surgery for Locally Advanced Breast CancerSun Hyun Bae, Won Par

9、k1, Seung Jae Huh1, Doo Ho Choi1, Seok Jin Nam2, Young-Hyuck Im3, Jin Seok Ahn3Department of Radiation Oncology, Korea Institute of Radiological & Medical Sciences, Seoul; Departments of 1Radiation Oncology, 2Surgery, and 3Division of Hematology-Oncology, Department of Medicine, Samsung Medical

10、Center, Sungkyunkwan University School of Medicine, Seoul, KoreaORIGINAL ARTICLEJ Breast Cancer 2012 September; 15(3: 329-336 /10.4048/jbc.2029Purpose: This study evaluated the treatment results and the necessity to irradiate the supraclavicular lymph node (SCN region in pat

11、hological N0-N1 (pN0-N1 patients with locally advanced breast cancer treated with neoadjuvant chemotherapy (NAC followed by surgery and radiotherapy (RT. Methods: Between 1996 and 2008, 184 patients with initial tumor size >5 cm or clinically positive lymph nodes were treated with NAC followed by

12、 surgery and RT. Among these patients, we retrospec-tively reviewed 98 patients with pN0-N1. Mastectomy was per-formed in 55%. The pathological lymph node stage was N0 in 49% and N1 in 51%. All patients received adjuvant RT to chest wall or breast and 56 patients (57% also received RT to the SCN reg

13、ion (SCNRT. Results: At 5 years, locoregional recurrence (LRR-free survival, distant metastasis-free survival, disease-free survival (DFS, and overall survival rates were 93%, 83%, 81%,and 91%, respectively. In pN0 patients, LRR was 7% in SCNRT group and 5% in SCNRT+ group. In pN1 patients, LRR was

14、7% in SCNRT- group and 6% in SCNRT+ group. There was no signif-icant difference of LRR, regardless of SCNRT. However, in pN1 patients, there were more patients with poor prognostic factors in the SCNRT+ group compared to SCNRT- group. These factors might be associated with worse DFS in the SCNRT+ gr

15、oup, even though RT was administered to the SCN region. Conclusion: Our study showed the similar LRR, regardless of SCNRT in pN0-pN1 breast cancer patients after NAC followed by surgery. Prospec-tive randomized trial is called for to validate the role of SCNRT.Key Words: Adjuvant radiotherapy, Breas

16、t neoplasms, Lymphatic irradiation, Neoadjuvant therapyCorrespondence: Won ParkDepartment of Radiation Oncology, Samsung Medical Center,Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 137-710, KoreaT el: +82-2-3410-2616, Fax: +82-2-3410-2619E-mail: wonro.parkReceived: May

17、8, 2012 Accepted: September 7, 2012J ournal of BreastCancer330 Sun Hyun Bae, et al. http:/ejbc.kr/10.4048/jbc.2029The recommended radiation field after NAC followed by surgery is breast or the chest wall and regional lymphatics. Recently, a study reported that isolated breas

18、t irradiation was enough for pN0 patients after NAC and breast conserving surgery (BCS 17.W e retrospectively investigated treatment outcomes accord-ing to SCNRT in pN0-N1 patients treated with NAC followed by surgery and adjuvant RT for locally advanced breast cancer and evaluated the necessity to

19、irradiate the SCN region.METHODSWe retrospectively reviewed the medical records of breast cancer patients treated with NAC followed by surgery and adjuvant RT for curative intent between 1996 and 2008 at Samsung Medical Center. We found 184 patients with initial tumor size >5 cm or with a clinica

20、lly positive axillary lymph node involvement without initial SCN or internal mammary lymph node metastasis. Of these, 98 patients with pN0-N1 after NAC were included in this study.The age at diagnosis ranged from 31 to 67 years (median, 44 years. Invasive ductal carcinoma (80 patients, 82% was the m

21、ost common histologic type. Clinical stage and pathological stage were classified according to the seventh edition of American Joint Committee on Cancer (AJCC Cancer Stag-ing 18. Clinical tumor size was evaluated with ultrasound. Clinical tumor stage at diagnosis was cT1 in 2 patients (2%, cT2 in 34

22、 (35%, cT3 in 47 (48%, and cT4 in 15 (15%. A clinically axillary lymph node involvement was defined by imaging studies or by clinical examination. Axillary lymph node metastasis was confirmed in 27 patients (32% by ultra-sound guided fine needle aspiration biopsy. Eighty-five patients (87% had initi

23、ally axillary lymph node metastasis. NAC involved anthracycline-based drugs in 42 patients (43%, taxane-based drugs in 9 patients (9%, and combined antha-cycline-taxane in 47 patients (48%, with a median of three NAC cycles (1-8 cycles. Modified radical mastectomy (MRM was performed in 54 patients (

24、55% and BCS was performed in 44 patients (45%. The median number of dissected axillary lymph nodes was 17 (range, 4-42. The pCR in both the prima-ry tumor and axillary lymph nodes was achieved in 11 patients (11%. The pathological stage was 0 in 15 patients (15%, I in 20 patients (21%, II in 49 pati

25、ents (50%, and III in 14 patients (14%. Adjuvant chemotherapy was administered to 79 patients (81%. Hormone therapy was administered to 52 patients (53%. Patients characteristics are summarized in Table 1.All patients received adjuvant RT to the breast or chest wall in tangential fields with a media

26、n dose of 50 Gy (range, 50-50.4 Gy at 1.8 to 2 Gy per fraction using 4- or 6-megavoltTable 1.Patients characteristics3511 (115 (96 (14>3587 (8951 (9136 (86Clinical T0.001cT1-236 (3713 (2323 (55cT3-462 (6343 (7719 (45Clinical NNSNegative 13 (136 (117 (17Positive 85 (8750 (8935 (83Surgery <0.001

27、MRM 54 (5538 (686 (14BCS 44 (4518 (3236 (86No. of DALNNS1755 (5630 (5625 (60>1743 (4426 (4617 (40Status of RMNSNegative 85 (8748 (8637 (88Others* 13 (138 (145 (12Pathology NSIDC 80 (8245 (8035 (83Others 18 (1811 (207 (17pCR NSYes 11 (114 (77 (17No 83 (8952 (9335 (83Pathological T0.001pT023 (246 (

28、1117 (40pT1-254 (5533 (5921 (50pT3-421 (2117 (304 (10Pathological N0.002pN048 (4920 (3628 (67pN150 (5136 (6414 (33Pathological stage<0.001015 (154 (711 (26I 20 (219 (1611 (26II 49 (5029 (5220 (48III 14 (1414 (250 (0Histologic gradeNSLow 8 (84 (74 (10Intermediate 38 (3923 (4115 (36High 25 (2519 (3

29、46 (14Unknown 27 (2810 (1817 (40Multiplicity 0.011Yes 12 (1211 (201 (2No 86 (8845 (8041 (98LVI 0.001Yes 27 (2823 (414 (10No 71 (7233 (5938 (90Status of ERNSNegative 55 (5629 (5226 (62Positive 43 (4427 (4816 (38Status of PRNSNegative 65 (6638 (6827 (64Positive 33 (3418 (3215 (36Hormone treatmentNSYes

30、 52 (5331 (5521 (50No 46 (4725 (4521 (50SCNRT=radiotherapy to the supraclavicular lymph node region; NS=not significant; MRM=modified radical mastectomy; BCS=breast conserving surgery; DALN=dis-sected axillary lymph node; RM=resection margin; IDC=invasive ductal carcinoma; pCR=pathologic complete re

31、sponse; LVI=lymphovascul a rspace invasion; ER= estrogen receptor; PR=progesterone receptor.*Others include positive or close (1 mm resection margin; Others include invasive lobular carcinoma, infiltrating cribriform carcinoma, invasive micropapillary carcinoma, mucinous carcinoma, infiltrating apoc

32、rine carcinoma, and metaplastic carcinoma.RT Field in pN0-N1 after NAC331 /10.4048/jbc.2029 http:/ejbc.krphoton beams. All patients who received whole breast irradia-tion also received an electron boost to the tumor bed (median dose 9 Gy, in 3 fractions. Internal mammary lym

33、ph node irradiation was not administered. Because of lack of consen-sus on the RT field after NAC, individual clinicians decided whether RT would be applied to the SCN region. RT to the SCN region was administered to 56 patients (57% (SCNRT+ group, while 42 (43% received RT to the breast or chest wa

34、ll only (SCNRT- group. In the SCNRT+ group, the SCNRT dose was 50 Gy in 25 fractions. Table 1 shows patients charac-teristics between the SCNRT+ and SCNRT- groups.BCS was more common in the SCNRT- group. Patients with the SCNRT+ group had more advanced cT and patho-logical tumor stage (pT, pN, and p

35、athological stage. The SCNRT- group had lower frequencies of a multiplicity and lymphovascular space invasion.We defined LRR as the appearance of local or regional tumor in the ipsilateral breast, chest wall, axilla, internal mam-mary, supraclavicular or infraclavicular area. SCN recurrence was defi

36、ned as any tumor recurrence in the supraclavicular or infraclavicular area. Distant metastasis (DM was defined as any recurrence other than LRR. LRR was confirmed using cytological aspiration or surgical excision.We compared the characteristics of the SCNRT+ and SCNRT groups using a chi-square test

37、or Fisher s exact test if the expected values are below 5. Survival rates were estimated with the Kaplan-Meier method and comparisons between the groups were determined using the log-rank test 19. We conducted subgroup analysis according to pN status, using Fishers exact test. All calculations were

38、performed using SPSS version 13.0 (SPSS Inc., Chicago, USA, and statistical signifi-cance was accepted for p -values of <0.05.RESUL TSPatterns of failureThe median follow-up period from the date of first cycle NAC was 42 months (range, 10-139 months. During follow-up, 19 patients (19% experienced

39、 failure, 6 had LRR, and 18 had DM. Among 6 patients with LRR, 5 patients had both LRR and DM; of these, 4 had synchronous LRR and DM. The remaining 1 patient had LRR only at the ipsilateral SCN. LRR sites were chest wall in 1 patient, axillary lymph node in 1 patient, internal mammary lymph node in

40、 1 patient, and SCN in 3 patients. Recurrence at the SCN was developed in 1 patient in the SCNRT- group and 2 patients in the SCNRT+ group. No additional SCN recurrence was observed after first failure detection.Table 2. Univariate analysis of locoregional recurrence-free survival (LR-RFS, disease-f

41、ree survival (DFS, and overall survival (OSAge (yr0.051NS<0.00135 77 6261>35 95 8395Clinical T stageNSNSNScT1-2 94 88 93cT3-4 93 7690Clinical N stageNSNSNSNegative 100 91100Positive 92 7990Surgery NS0.005NSMRM 90 69 86BCS 96 9095pCR NSNSNSYes 100100100No 92 7890Pathological T stageNS0.0070.006

42、pT0100100100pT1-2 90 78 93pT3-4 95 6776Pathological N stageNS0.034NSpN0 93 91 93pN1 93 7090Pathological stageNS0.028NS0100100100I 89 89 91II 91 77 92III 100 6479Histologic gradeNSNSNSLow 100 73100Intermediate 89 77 95High 95 7988Multiplicity NS0.029NSYes 80 58 92No 95 8491LVI NSNSNSYes 96 66 96No 92

43、 8689Hormone treatmentNSNS0.019Yes 96 88 98No 90 7384SCNRT NS0.012NS Yes 94 72 89No 929294NS=not significant; MRM=modified radical mastectomy; BCS=breast conserv-ing surgery; pCR=pathologic complete response; LVI=lymphovascularspace invasion; SCNRT=radiotherapy to the supraclavicular lymph node regi

44、on.SurvivalAt 5-years, the LRR-free survival (LRRFS rate, the DM- free survival (DMFS rate, and the disease-free survival (DFS rate were 93%, 83%, and 81%, respectively. The overall survival (OS rate at 5-years was 91%. On univariate analysis, patients age, surgery type, pT, pN, pathological stage,

45、multiplicity,332 Sun Hyun Bae, et al. http:/ejbc.kr/10.4048/jbc.2029hormone treatment and SCNRT were significant factors for survivals (Table 2. According to the SCNRT, 5-year DFS was 72% and 92% in the SCNRT+ and SCNRT- groups, respectively.Subgroup analysisTable 3 shows th

46、e patients characteristics between the SCNRT- and SCNRT+ groups according to pN stage. In 48 patients with pN0 after NAC, there was no significant differ-ence in prognostic factors between the SCNRT- and SCNRT+ groups except surgery type (MRM vs. BCS. Locoregional recurrence was 7% in SCNRT- group a

47、nd 5% in SCNRT+ group. Patients age was the only significant factor for LRRFS (Table 4. Surgery type and pT were significant factors for DFS. The patients with pN0 had similar LRRFS and DFS, regardless of SCNRT (Figure 1.In 50 patients with pN1 after NAC, there was a significant difference in progno

48、stic factors between the SCNRT- and SCNRT+ groups. SCNRT+ group had more advanced cT, more frequent multiplicity and more advanced pathological stage. Especially, all patients with pathologic stage III received RT to the SCN region. Locoregional recurrence was 7% in SCNRT- group and 6% in SCNRT+ gro

49、up. Multiplicity was the only significant factor for LRRFS. Clinical tumor stage and SCNRT were significant factors for DFS. The patients with pN1 had similar LRRFS, regardless of SCNRT, but worse DFS in SCNRT+ groups (Figure 2.DISCUSSIONOur study showed favorable survival rates for NAC followed by

50、surgery compared to those of published randomized studies such as the National Surgical Adjuvant Breast and Bowel Proj-ect (NSABP B-18 and the European Organization of Research and Treatment of Cancer (EORTC 10902 trials 11,13. These previous studies reported approximately 10% LRR. Recent studies re

51、ported a good response to NAC with lower LRR rates. McGuire et al. 20 investigated the role of postmastec-tomy RT in patients with breast cancer who achieved a pCR to NAC. They reported 10-year LRR rates in patients with breast cancer who achieved a pCR to NAC and received adju-vant RT and in nonirr

52、adiated patients were 5% and 10%, respectively. Le Scodan et al. 21 evaluated the effect of post-mastectomy RT in stage II-III breast cancer patients with pN0 after NAC and reported that 10 patients (8% developed LRR; 3 patients (4% who received RT and 7 (12% who did not. The results showed no incre

53、ase in the risk of LRR, DM or death when RT was omitted. We observed 6% overall LRR in patients with N0-N1 after NAC followed by surgery and adju-vant RT; 3 patients (7% in the SCNRT- group and 3 patients (5% in the SCNRT+ group, demonstrating similar locore-gional control to that observed in previo

54、us studies.NAC is commonly used to increase the chance for breast conservation and to intend to improve treatment outcome,Table 3. Patients characteristics between the SCNRT+ and SCNRT-groups according to pN stage35 36 2 0>3517223414Clinical T stageNS0.002cT1-2 3121011cT3-41716263Clinical N stage

55、NSNSNegative 5 7 1 0Positive 15213514Surgery 0.031<0.001MRM 11 627 0BCS 922914pCR NS-Yes 4 7 0 0No16213614Pathological T stageNS0.001pT0 411 2 6pT1-2111322 8pT3-4 5412Pathological stage NS0.0150 411 0 0I 7 9 2 2II 7 82212III2 012Multiplicity NS0.022Yes 0 111 0No20272514Hormone treatment NSNSYes 1

56、11520 6No 913168LRR NSNSYes 1 2 2 1No 19263413DF NSNSYes 3 213 1No 17262313Death NSNSYes 1 2 5 0No19263114SCNRT=radiotherapy to supraclavicular lymph node region; NS=not signifi-cant; MRM=modified radical mastectomy; BCS=breast conserving surgery; pCR=pathologic complete response; LRR=locoregional r

57、ecurrence; DF= disease failure.RT Field in pN0-N1 after NAC333 /10.4048/jbc.2029http:/ejbc.krTable 4.Univariate analysis of locoregional recurrence-free survival (LRRFS, disease-free survival (DFS according to pathologic nodal stageAge (yr0.0230.029NSNS35 73 65100 50>3597979371Clinical T stageNSNSNS0.011cT1-2 91 85 95 90cT3-494949155Clinical N stageNSNSNSNSNegative 100100100 0Positive 91889372Surgery NS0.041NSNSMRM 88 96 92 82BCS 96829561pCR NSNS.Yes 100100. . No91899370Pathological T stageNS0.039NSNSpT0100100100100pT1