No clear effect of postoperative radiotherapy on survival of breast cancer patients with one to three positive nodes: a population-based study

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1 Annals of Oncology original articles Annals of Oncology 26: , 2015 doi: /annonc/mdv159 Published online 3 April 2015 No clear effect of postoperative radiotherapy on survival of breast cancer patients with one to three positive nodes: a population-based study A. E. Nordenskjöld 1,2, H. Fohlin 3,4, P. Albertsson 2, L. G. Arnesson 5, C. Chamalidou 1,2, Z. Einbeigi 2, E. Holmberg 6, B. Nordenskjöld 4 & P. Karlsson 2 *, the Swedish and Southeastern Breast Cancer Groups 1 Department of Medicine, Southern Älvsborg Hospital, Borås; 2 Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrenska University Hospital, Gothenburg; 3 Regional Cancer Center South East Sweden, Linköping; 4 Department of Clinical and Experimental Medicine and Department of Oncology, Linköping University, Linköping; 5 Department of Surgery, University Hospital, Linkoping; 6 Regional Cancer Center, Gothenburg, Sweden Received 13 December 2014; revised 12 March 2015; accepted 16 March 2015 Background: In published radiotherapy trials, the failure rate in the control arm among patients with one to three positive nodes is high compared with that seen with modern adjuvant treatments. Therefore, the generalizability of the results has been questioned. The aim of the present study was to compare relative survival in breast cancer patients between two Swedish regions with screening mammography programs and adjuvant treatment guidelines similar with the exception of the indication of radiotherapy for patients with one to three positive nodes. Patients and methods: Between 1989 and 2006, breast cancer patients were managed very similarly in the west and southeast regions, except for indication for postoperative radiotherapy. In patients with one to three positive nodes, postmastectomy radiotherapy was generally given in the southeast region (89% of all cases) and generally not given in the west region (15% of all cases). For patients with one to three positive nodes who underwent breast-conserving surgery, patients in the west region had breast radiotherapy only, while patients in the southeast region had both breast and lymph nodes irradiated. Results: The 10-year relative survival for patients with one to three positive lymph nodes was 78% in the west region and 77% in the southeast region (P = 0.12). Separate analyses depending on type of surgery, as well as number of examined nodes, also revealed similar relative survival. Conclusion: Locoregional postoperative radiotherapy has well-known side-effects, but in this population-based study, there was little or no influence of this type of radiotherapy on survival when one to three lymph nodes were involved. Key words: postoperative radiotherapy, breast cancer, positive nodes introduction It is well known that radiotherapy effectively reduces the locoregional recurrence rate and also prolongs breast cancer-specific survival [1, 2]. Recently, it was shown that radiotherapy after breast-conserving therapy reduces the overall death rate at 15 years by 3.8%: from 25.2% to 21.4% [3]. The effectiveness of postmastectomy radiotherapy in patients with one to three positive nodes is still heavily debated. On the one hand, several randomized studies have shown clear benefits for patients with one to three positive nodes [2, 4 6]; on the other hand, the high locoregional recurrence rate in the control arm of these trials *Correspondence to: Prof. Per Karlsson, Department of Oncology, Sahlgrenska University Hospital, Röda stråket 16, S Gothenburg, Sweden. Tel: ; Fax: ; per.karlsson@oncology.gu.se might not be representative of breast cancer patients with one to three positive nodes in the present era of modern adjuvant treatment and screening mammography programs. The generalizability of the positive results for patients with one to three positive nodes has been questioned, which can be seen in the last round of voting of the St Gallen breast cancer panel, where only one-third of the panelists voted for postmastectomy radiotherapy for all patients with one to three positive nodes [7]. Furthermore, a study from MD Anderson reported that in an era of modern adjuvant treatment ( ), patients with one to three positive nodes without risk features had a very low rate of locoregional recurrence even without radiotherapy [8]. Symptoms from the arm are still quite common after locoregional treatment [9, 10], and late effects of radiotherapy can begin and progress decades after treatment. Examples of such effects are cardiac disease, brachial plexus neuropathy, arm The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com.

2 original articles Annals of Oncology lymphedema, rib fractures, and impaired shoulder motion [11]. It is therefore important to carefully consider radiotherapy target volumes and indications for radiotherapy. The aim of the present study was to analyze the influence of radiotherapy on relative survival among breast cancer patients with one to three positive nodes. We compared two similar Swedish regions with approximately the same breast cancer management, with the exception of an indication of radiotherapy for patients with one to three positive nodes. materials and methods cancer registration In Sweden, cancer care for the 9 million inhabitants is organized into six health care regions. In each region, there is a regional cancer center responsible for cancer registration and cancer management programs. In Sweden, it In the cancer register diagnosed has been compulsory since 1958 for both the treating physician and the pathologist/cytologist to independently notify the Swedish cancer register (SCR) of all new incidences of cancer. The SCR receives reports containing the ICD code of the malignancy, the histological systematized nomenclature of medicine (SNOMED) code, the TNM stage of the disease, the date of diagnosis, the date of birth for the patient, and the personal identification number unique to each individual in Sweden. The completeness of the national register is about 96% [12]. The majority of the patients are also regionally registered in a quality-management register. These registers contain more detailed information of incident tumor characteristics and primary treatment. For breast cancer, >95% of the patients are treated according to the management programs and registered in the regional quality-management register databases associated with the programs [13]. cohorts We selected patients with one to three positive nodes: 2750 (15%) from the W region and 1698 (15%) from the SE region as illustrated in Figure 1. Excluded Not registrated in the regional breast cancer register In the regional breast cancer register Primary operated and no distant metastases <75 years old lymph node metastases Not primary operated or distant metastases years old 1979 No lymph node metastases 5464 >3 lymph node metastases Breast surgery Breast surgery not specified Figure 1. Consort diagram of cohorts from the west and southeast regions. All registered incident breast cancer cases in the Swedish Cancer Register from these two regions from 1989 to 2006 comprised the initial study base. From the total cases, all primarily operated cases without initial distant metastases and age <75 years with one to three positive lymph nodes were selected Nordenskjöld et al. Volume 26 No. 6 June 2015

3 Annals of Oncology original articles These patients were followed up for vital status until August 2010 through record linkage to national population registers. We retrieved information from the quality-management register regarding age at diagnosis; type of surgery; tumor size; number of examined nodes; hormone receptor status; grade; and adjuvant therapy regarding radiotherapy (Yes/No), endocrine therapy (Yes/No), and chemotherapy (Yes/No). Tumor and patient characteristics, as well as adjuvant treatments for those with one to three metastatic nodes, are shown in Table 1. therapy Surgery, radiotherapy, adjuvant endocrine therapy, and chemotherapy were delivered according to guidelines regularly updated based on St Gallen recommendations [14]. In the SE region, after mastectomy or breast-conserving therapy, women with node-positive disease generally received radiotherapy to the breast or chest wall and also to the axilla and, in most cases, to the supraclavicular lymph nodes. In the W region, at least four metastatic lymph nodes were required during the period for the delivery of postoperative lymph node radiotherapy and postmastectomy chest wall radiotherapy. Patients who underwent breast-conserving surgery generally had breast radiotherapy in both the SE and W regions. In both regions, the patients received modern computed tomography (CT) based dose planning for radiotherapy. statistical methods Relative survival was computed using the Ederer II method [15]. Mortality data for the general population in Sweden were used to estimate expected survival rates for the study populations. The mortality data comprised the probability of death for single-year age groups in 1-year calendar periods. Stata statistical software was used to calculate relative survival. Survival time was calculated from date of diagnosis to 15 August 2010 or to date of death if it occurred before that date. Relative risk between different groups was estimated by Poisson regression. A P value of <0.05 was considered to be statistically significant. All statistical analyses were carried out with Stata/SE results In the W region, 15% (225/1490) of the patients with one to three positive nodes had postmastectomy radiotherapy and 87% (1099/1260) of the patients who underwent breast-conserving surgery and had one to three positive nodes received breast radiotherapy. The corresponding figures for patients with one to Table 1. Patient, tumor, and treatment characteristics for patients in the southeast and west regions of Sweden with one to three positive lymph nodes diagnosed Characteristics Surgery and region, N (%) Breast-conserving Mastectomy Total Southeast West Southeast West Total patients Age, years < (32) 416 (33) 298 (29) 474 (32) 1406 (32) (68) 844 (67) 714 (71) 1016 (68) 3042 (68) Tumor size (mm) (14) 195 (16) 71 (7) 88 (6) 446 (10) (57) 664 (54) 360 (36) 473 (33) 1881 (43) > (30) 376 (30) 566 (57) 891 (61) 2034 (47) Unknown ER status Negative 130 (25) 185 (16) 217 (28) 268 (19) 800 (21) Positive 394 (75) 1005 (84) 560 (72) 1110 (81) 3069 (79) Unknown PR status Negative 136 (26) 373 (31) 274 (35) 495 (36) 1278 (33) Positive 389 (74) 813 (69) 501 (65) 882 (64) 2585 (67) Unknown NHG I 96 (21) 199 (27) 76 (13) 133 (17) 504 (20) II 232 (51) 340 (46) 278 (48) 383 (49) 1233 (48) III 131 (29) 202 (27) 231 (39) 261 (34) 825 (32) Unknown Endocrine therapy Yes 450 (66) 689 (55) 571 (56) 793 (53) 2503 (56) Radiotherapy Yes 657 (96) 1099 (87) 905 (89) 225 (15) 2886 (65) Chemotherapy Yes 179 (26) 505 (40) 242 (24) 662 (44) 1588 (36) ER, estrogen receptor; PR, progesterone receptor; NHG, Nottingham histological grade. Volume 26 No. 6 June 2015 doi: /annonc/mdv

4 original articles three positive nodes in the SE region were 89% (905/1012) for postmastectomy radiotherapy and 96% (657/686) for breast and regional radiotherapy after breast-conserving surgery. The median number of examined lymph nodes among patients with one to three positive nodes was 13 in the W region and ten in the SE region. The distribution of lymph nodes examined is shown in Figure 2. The use of adjuvant endocrine therapy was similar between the regions: W region, 54% (1482/2750) and SE region, 60% (1021/1698). Adjuvant chemotherapy was slightly more common in the W region, 42% (1167/2750) compared with 25% (421/1698) in the SE region. The relative survival of patients with one to three positive lymph nodes in the two regions was similar (Figure 3). The 10- year relative survival was 78% in the W region and 77% in the SE region (P = 0.12), Separating the relative survival analyses for patients with mastectomy and those with breast-conserving surgery resulted in similar results for the two regions (Figure 4). Since the number of examined lymph nodes differed by region, Percentage Total Unknown Lymph nodes analyzed Figure 2. Distribution of number of axillary lymph nodes analyzed in patients with one to three positive nodes in the west (n = 2750) and southeast (n = 1698) regions. Cumulative probability 0 5 P = Figure 3. Relative survival of all patients with one to three positive nodes from the west (n = 2750) and southeast (n = 1698) regions. separate analyses divided by number of examined lymph nodes were also carried out for patients with mastectomy (Figure 5) and those with breast-conserving surgery (Figure 6). There were no significant survival differences between the regions (Figures 5 and 6). The guidelines were identical between the two regions with respect to radiotherapy for patients without lymph node involvement, as well as for those with >3 positive nodes. A relative survival comparison of these two groups yielded almost identical relative survival outcomes between the two regions (data not shown). discussion Annals of Oncology In this population-based study, which compared two similar Swedish regions with very similar breast cancer management except for the indication of radiotherapy for patients with one to three positive nodes, survival was very similar in spite of the difference in postoperative radiotherapy indication. This is in contrast to the data from the Early Breast Cancer Trialists Collaborative Group (EBCTCG) [2, 3], which showed that radiotherapy prolonged survival. This might be partly explained by the use of standardized surgery and modern systemic treatment in the two Swedish regions during this period, which have also yielded a general better outcome in these cohorts compared with the survival in the EBCTCG meta-analysis. The outcome in this study of Swedish cohorts with one to three positive nodes is similar to the outcomes of groups without lymph node involvement in the EBCTCG analysis, in which no apparent effect was seen for postmastectomy radiotherapy. In randomized studies, adjuvant radiation therapy has been shown to reduce the risk of locoregional recurrence by 70%. It has been clearly demonstrated in clinical trials that for nodepositive patients, radiotherapy after undergoing either breastconserving surgery or mastectomy not only reduces local recurrences but also improves long-term survival [1]. This was confirmed in two other studies, which demonstrated that additional regional nodal irradiation reduces the risk of locoregional and distant recurrence and improves overall survival [16, 17]. We also look forward to the results of the SUPREMO trial, in which patients with one to three positive lymph nodes were included and randomized to radiotherapy or no radiotherapy [18]. In this study, we used relative survival to measure outcome. In a previous study from the SE region, relative survival and breast cancer-specific survival were shown to be very similar after 5, 10, and 15 years of observation [13]. By using relative survival, we were not dependent on validated data from followup visits. There is evidence from the EBCTCG meta-analysis that there is an increased risk of cardiac deaths linked to mean cardiac doses over 5 Gy. However, we do not think that increased cardiac death rate influenced our data, since CT-based dose planning and modern linear accelerators were used [1]. The lower number of nodes analyzed may explain, at least in part, the slightly worse outcome for SE region patients with one to three metastatic nodes, since some of them may have had undetected metastatic nodes. However, stratifying the analyses between the regions by the number of examined lymph nodes did not reveal any survival advantage for the SE region, which 1152 Nordenskjöld et al. Volume 26 No. 6 June 2015

5 Annals of Oncology original articles Mastectomy Breast-conserving surgery Cumulative probability 0 5 generally treated patients with one to three positive nodes with postoperative radiotherapy. There was more adjuvant chemotherapy in the W region (42%) compared with the SE region (25%) during the period under study. On the other hand, there were more endocrine treatments in the SE region compared with the W region (60% versus 54%, respectively). A limitation of the registration of the adjuvant treatment was that only the therapy that was initially started was reported; thus, no information on compliance could be abstracted from the register and intention-to-treat information regarding adjuvant treatment was used for the comparison. Between the regions, no difference in survival was seen for either N0 patients or those with >3 metastatic nodes; for both of these P = 0.36 P = Figure 4. Relative survival of patients with one to three positive nodes divided by type of surgery. Mastectomy: west (n = 1490) and southeast (n = 1012) regions. Breast-conserving surgery: west (n = 1260) and southeast (n = 686) regions. Cumulative survival 1 5 nodes analyzed 6 10 nodes analyzed P = 0.69 P = nodes analyzed 16 nodes analyzed P = P = Figure 5. Relative survival of patients with one to three positive nodes who underwent mastectomy. Patients separated according to the number of lymph nodes analyzed: 1 5 nodes analyzed, west (n = 99) and southeast (n = 136) regions; 6 10 nodes analyzed, west (n = 429) and southeast (n = 432) regions; nodes analyzed, west (n = 445) and southeast (n =302) regions; and >15 nodes analyzed, west (n = 510) and southeast (n = 139) regions. Cumulative survival 1 5 nodes analyzed 6 10 nodes analyzed P = 0.46 P = nodes analyzed 16 nodes analyzed P = 0.39 P = Figure 6. Relative survival of patients with one to three positive nodes who underwent breast-conserving surgery. Patients separated according to the number of lymph nodes analyzed: 1 5 nodes analyzed, west (n = 121) and southeast (n = 95) regions; 6 10 nodes analyzed, west (n = 333) and southeast (n = 297) regions; nodes analyzed, west (n = 367) and southeast (n = 205) regions; and >15 nodes analyzed, west (n = 433) and southeast (n = 87) regions. groups, indications for radiotherapy were identical between the regions. Thus, the relative effect of the minor difference in adjuvant medical treatment between the regions seems to be of limited importance in this comparison. The American Society of Clinical Oncology (ASCO) special article Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology recommends that patients with 4 positive axillary lymph nodes undergo postmastectomy radiotherapy [19]. For patients with one to three positive lymph nodes, there are no recommendations or suggestions with respect to the routine use of postmastectomy radiotherapy in patients with T1 or T2 tumors. This recommendation is supported by the results of this study. Volume 26 No. 6 June 2015 doi: /annonc/mdv

6 original articles Locoregional failures are a notable problem for patients who undergo mastectomy alone, as well as for some patients with node-negative breast cancer and some subgroups of patients with node-positive disease who receive adjuvant treatment [5]. In addition to the number of positive lymph nodes, predictors of locoregional failures include tumor-related factors, such as vascular invasion, higher grade, and larger size, as well as younger age. On the basis of our results, we suggest that, for patients with one to three positive nodes, these predictors should be considered before postmastectomy or lymph node radiotherapy is generally recommended. This suggestion is also in line with the recurrence patterns observed by the International Breast Cancer Study Group [20, 21] and by Strom et al. [22]. Several factors may have contributed to the prolonged survival of our cohort and to the fact that there was at most a limited effect of radiotherapy on survival in this study. Surgeries in both regions were carried out by specialized breast surgeons, and endocrine therapy and chemotherapy were available according to St Gallen recommendations. Additionally, in contrast to most patients in breast cancer trials, the majority of the patients in both regions had participated in population-based mammography-screening programs, which are known to reduce the breast cancer death rate. funding This study was supported by grants without numbers from the King Gustav the Vth Jubilee Clinic Cancer Foundation in Gothenburg and from Swedish governmental grants to scientist working in health care (ALF) and the Swedish Cancer Foundation. disclosure The authors have declared no conflicts of interest. references 1. Clarke M, Collins R, Darby S et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366: EBCTCG (Early Breast Cancer Trialists Collaborative Group), McGale P, Taylor C et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 2014; 383: Early Breast Cancer Trialists Collaborative GroupDarby S, McGale P et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011; 378: Ragaz J, Olivotto IA, Spinelli JJ et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 2005; 97: Annals of Oncology 5. Overgaard M, Hansen PS, Overgaard J et al. Postoperative radiotherapy in highrisk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997; 337: Overgaard M, Jensen MB, Overgaard J et al. Postoperative radiotherapy in highrisk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999; 353: Goldhirsch A, Winer EP, Coates AS et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer Ann Oncol 2013; 24: McBride A, Allen P, Woodward W et al. Locoregional recurrence risk for patients with T1,2 breast cancer with 1 3 positive lymph nodes treated with mastectomy and systemic treatment. Int J Radiat Oncol Biol Phys 2014; 89: Lundstedt D, Gustafsson M, Malmstrom P et al. Symptoms years after breast cancer radiotherapy data from the randomised SWEBCG91-RT trial. Radiother Oncol 2010; 97: Lundstedt D, Gustafsson M, Steineck G et al. Long-term symptoms after radiotherapy of supraclavicular lymph nodes in breast cancer patients. Radiother Oncol 2012; 103: Johansson S, Svensson H, Denekamp J. Dose response and latency for radiationinduced fibrosis, edema, and neuropathy in breast cancer patients. Int J Radiat Oncol Biol Phys 2002; 52: Barlow L, Westergren K, Holmberg L, Talback M. The completeness of the Swedish Cancer Register: a sample survey for year Acta Oncol 2009; 48: Tejler G, Norberg B, Dufmats M et al. Survival after treatment for breast cancer in a geographically defined population. Br J Surg 2004; 91: Goldhirsch A, Wood WC, Coates AS et al. Strategies for subtypes dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer Ann Oncol 2011; 22: Ederer F, Axtell LM, Cutler SJ. The relative survival rate: a statistical methodology. Natl Cancer Inst Monogr 1961; 6: Struikmans H, Collette S, Van den Bogaert W et al. Lymph node RT improves survival in Breast Cancer: 10 years results of the EORTC ROG and BCG phase III trial 22922/ In ESTRO 33. Vienna: EOTRC, Whelan TJ, Olivotto I, Ackerman I et al. NCIC-CTG MA.20: an intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol 2011; 29: LBA Kunkler IH, Canney P, van Tienhoven G et al. Elucidating the role of chest wall irradiation in intermediate-risk breast cancer: the MRC/EORTC SUPREMO trial. Clin Oncol (R Coll Radiol) 2008; 20: Recht A, Edge SB, Solin LJ et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19: Karlsson P, Cole BF, Chua BH et al. Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report. Ann Oncol 2012; 23: Karlsson P, Cole BF, Price KN et al. The role of the number of uninvolved lymph nodes in predicting locoregional recurrence in breast cancer. J Clin Oncol 2007; 25: Strom EA, Woodward WA, Katz A et al. Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy. Int J Radiat Oncol Biol Phys 2005; 63: Nordenskjöld et al. Volume 26 No. 6 June 2015