Ir J Med Sci DOI 10.1007/s11845-015-1246-0
ORIGINAL ARTICLE
Management of the axilla: has Z0011 had an impact? D. P. Joyce • A. J. Lowery • L. B. McGrath-Soo E. Downey • L. Kelly • G. T. O’Donoghue • M. Barry • A. D. K. Hill
•
Received: 10 April 2014 / Accepted: 31 December 2014 Ó Royal Academy of Medicine in Ireland 2015
Abstract Background Management of axillary disease in breast cancer has evolved significantly over the last two decades with the introduction of SLNB and a trend towards less radical surgery. Data from the American College of Surgeons Oncology Group Z0011 trial proposes that not all patients with positive axillary lymph nodes require completion axillary dissection. Aims The aim of this study was to determine whether there has been a change in practice patterns for axillary management in Ireland since the publication of this ‘practice-changing’ trial. Methods A review of breast cancers managed in the 12 months prior to publication of Z0011 (pre-Z0011) and comparison with those managed in the following 12 months (post-Z0011) was undertaken in three tertiary referral breast cancer centres. Patients with a positive SLNB were identified, and clinicopathologic data and subsequent management was compared between the two cohorts.
Results There were 708 SLNB performed during the study period; 326 pre-Z0011 and 382 post-Z0011. There was no difference in the rate of SLN positivity between the two cohorts: 29.1 % had a positive SLN pre-Z0011 and 29.3 % were positive post-Z0011. There were a significantly lower number of axillary clearances performed in SLN-positive patients in the post-Z0011 period (71.4 %) compared to the pre-Z011 period (93.7 %, p = 0.0022 Chi-square). Of the patients with tumour characteristics meeting the Z0011 inclusion criteria in the initial 12 months of the study, 92.3 % underwent ALND compared with 65.6 % in the final 12 months of the study (p = 0.0006 Chi-square). Conclusions There has been a change in clinical practice since the publication of the Z0011 trial, illustrated by a decrease in the rate of axillary clearance in node-positive breast cancers. Keywords Breast cancer Axilla Sentinel lymph node biopsy Axillary lymph node dissection ACOSOG Z0011
Introduction D. P. Joyce (&) A. J. Lowery L. B. McGrath-Soo E. Downey A. D. K. Hill Department of Breast and Endocrine Surgery, Beaumont Hospital, Dublin 9, Ireland e-mail: [email protected] L. Kelly Department of Breast Surgery, Cork University Hospital, Cork, Ireland G. T. O’Donoghue Department of Breast Surgery, Waterford Regional Hospital, Waterford, Ireland M. Barry Department of Breast Surgery, Mater Hospital, Dublin 7, Ireland
Management of the axilla in patients with breast cancer has evolved significantly in recent decades. The sentinel lymph node biopsy (SLNB) has become the standard of care for axillary staging in clinically node-negative patients [1, 2]. This procedure is associated with less short-term and longterm side effects than axillary lymph node dissection [3, 4]. Patients with a positive SLNB have been shown to be at risk of further axillary metastases, earlier disease recurrence and decreased overall survival. As a result, patients with a positive SLNB in the setting of breast cancer have traditionally been managed with axillary lymph node dissection (ALND) [5–10].
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Current NICE guidelines recommend that patients with early invasive breast cancer and either micrometastases or macrometastases on SLNB proceed to ALND [11]. Recent studies have suggested that patients with isolated tumour cells (ITCs) only identified at SLNB should be regarded as lymph node-negative and as such they can be spared ALND [11, 12]. However, the ACOSOG Z0011 trial proposes that not all patients with positive axillary lymph nodes identified at SLNB require completion ALND [13]. This trial was designed to determine whether ALND impacted on survival in selected SLN-positive breast cancer patients. Patients were randomised to either SLNB alone or SLNB followed by ALND. All patients were treated with wide local excision followed by breast irradiation. No difference in 5-year overall or disease-free survival was demonstrated between the two groups [14]. The authors concluded that SLNB alone does not result in inferior survival in patients with limited sentinel lymph node metastatic disease treated with WLE and systemic therapy compared to those treated with ALND [14]. The publication of this trial generated significant debate and discussion in the breast surgical oncology community leading to reports of changes in practice depending on institutional preferences [15]. This change in practice may be reasonable in the subset of patients who satisfy the ACOSOG Z0011 trial criteria; however, the omission of ALND in all patients with positive SLNBs is controversial. There has been no official change in guidance pertaining to the management of axillary disease by the National Cancer Control Programme (NCCP) in Ireland. The aim of this study was to determine the impact of Z0011 data on surgical practice and identify whether there has been a change in practice patterns for axillary management in an Irish population since the publication of the ACOSOG Z0011 trial.
Methods This study was carried out in three tertiary referral breast cancer centres: Beaumont Hospital (Dublin), Cork University Hospital, and Waterford Regional Hospital. In order to compare practices with regard to the management of the axilla pre- and post-publication of the ACOSOG Z0011 trial patients were divided into two groups according to the date of breast cancer treatment. The pre-Z0011 group, correspond to the group of patients who were treated in the 12 months prior to publication of the ACOSOG Z0011 trial (March 2010–February 2011). The post-Z0011 cohort includes patients who were treated in the 12 months following the publication of the Z0011 trial between March 2011 and February 2012. Data in each of the three participating centres were extracted from a prospectively maintained national database (Dendrite Clinical Systems
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Ltd, Oxford, UK) in which clinical, radiological and pathological data are recorded for all patients attending triple assessment breast clinics. The outcome of multidisciplinary team discussion for any patients with breast pathology is also recorded prospectively in this database. Data obtained included patient demographics, age, gender, tumour size, number of positive sentinel lymph nodes and the size of sentinel lymph node metastases, and further axillary management. All sentinel lymph node biopsies were processed in a standardised fashion as follows: sentinel lymph nodes were measured and trimmed of fat; nodes were sectioned at 2 mm intervals perpendicular to the long axis; following overnight processing they were cut at three levels at 50 lm intervals for preparation of H&E stained sections; a spare section was cut at each level; Cytokeratin AE1/3 immunostain was performed on one of spare sections. Positive sentinel lymph nodes were defined as metastasis seen on standard H&E staining (as per the Z0011 criteria). Patients with ITC or metastasis seen only on immunohistochemistry were considered SLN negative. Data entry into the Dendrite database in each breast unit was performed by a dedicated data manager who had no interaction with patients and surgeons in order to ensure confidentiality and minimise bias in our dataset. Comparisons were made between groups using Chisquare for categorical variables and independent t test for means. Data analysis was performed using SPSS Version 12.
Results A total of 708 sentinel lymph node biopsies were performed during the 2-year period of the study. Three hundred and twenty-six were performed in the pre-Z0011 era and 382 in the 12 months following the publication of Z0011. There was no statistically significant difference in the rate of sentinel lymph node positivity between the two groups with 29.1 % (n = 95) of patients pre-Z0011 having a positive SNLB compared with 29.3 % (n = 112) postZ0011 (p = 1 Chi-square). A total of 89 patients (93.7 %) who had lymph node metastases identified on SLNB proceeded to ALND in the initial 12 months of the study. However, a significantly lower proportion underwent this procedure following the publication of Z0011 (n = 80, 71.4 %, p = 0.0022 Chisquare). Of the patients who had positive SLNB in the initial 12 months of the study, 54.7 % (n = 52) fit the Z0011 eligibility criteria. Similarly 54.5 % (n = 61) of patients were Z0011 eligible in the final 12 months of the study. Examination of these subgroups identified a significant change in practice with respect to the axilla in patients who had a positive SLNB. In the first 12 months of the study 48
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of the 52 (92.3 %) patients who would have been eligible for inclusion in the ACOSOG Z0011 trial proceeded to completion lymph node dissection. However, the group of patients who were treated following the publication of the results of Z0011 had a statistically significantly lower rate of ALND with only 40 out of 61 patients (65.6 %) undergoing this procedure (p = 0.0006 Chi-square). Pre-Z0011 cohort The clinicopathologic data pertaining to patients in the preand post-Z0011 cohorts are outlined in Table 1. In the preZ0011 cohort, patients who did not undergo ALND were older than those who proceeded to ALND (mean 73.5 vs. 52.1 years, p = 0.0034). The clinical tumour size in the non-ALND group was smaller than that of the ALND group (mean tumour size 29.1 vs. 31.9 mm, p = 0.0016. There was no difference in the rates of oestrogen receptor (ER) positivity between the ALND and non-ALND groups (92.1 vs. 100 %, p = 0.4751). Post-Z0011 cohort In the post-Z0011 cohort, the mean age of patients undergoing ALND was younger than those who did not proceed to ALND (mean 54.7 vs. 63.2 years, p \ 0.00001). The mean tumour size in the non-ALND group was smaller than in the ALND group (mean 26.3 vs. 31.0 mm, respectively, p \ 0.00001). In terms of ER status, there was no difference in the rates of ER positivity between the two groups (91.3 % in the ALND vs. 93.8 % in the non-ALND group, p = 0.6629).
Discussion The use of SLNB as a method of staging the axilla in patients with invasive breast cancer has radically changed practice since its introduction in the 1990s [16]. Thus far, patients with a positive SLNB have proceeded to ALND, a procedure which is associated with significant morbidity including lymphoedema and reduced arm movement [17]. However, in recent years there has been a trend towards Table 1 Clinicopathologic features of SLN-positive patients who did and did not undergo ALND pre- and postZ0011
less radical surgery not only in terms of our management of the breast, but also with regard the axilla. The ACOSOG Z0011 trial was established to investigate if ALND may be avoided in patients with sentinel lymph node metastases. The study showed that SLNB alone without ALND resulted in lower rates of locoregional recurrence with 5-year disease-free survival (DFS) of 82.2 % in the ALND group compared with 83.9 % in the SLNB alone group. Similarly, the Z0011 trial showed no difference in 5-year overall survival (OS) between the two arms of the study (91.8 % in the ALND group versus 92.5 % in the SLNB alone group) [17]. The results of this trial have generated a significant amount of controversy mainly in relation to the early closure of the study, a point which the investigators explained by the slow recruitment of participants. Length of followup has also been highlighted as a potential area of weakness in this study. However, given that median time to axillary recurrences in both NSABP B-04 [18] and ACOSOG Z0010 [19] was less than the median follow-up of 6.3 years in Z0011, the authors were of the opinion that length of follow-up was sufficient to identify the majority of axillary recurrences [17]. Some critics of Z0011 have highlighted that the majority of patients were postmenopausal and had ER-positive tumours and therefore questioned the validity of the study findings in the setting of premenopausal patients with ER-negative breast cancer. However, additional analysis of the patients included in the Z0011 trial showed no difference in outcomes between the two arms of the study for either premenopausal women or those with ER-negative tumours [17]. Similarly the EORTC AMAROS trial was established to investigate if axillary radiotherapy may offer a comparable alternative to ALND in cases of a positive SLNB. Patients included in this study were those with clinically nodenegative breast cancer. Patients in the axillary radiotherapy group were found to have similar axillary recurrence rates compared to the ALND group (1.03 vs. 0.54 %). Furthermore, no significant differences were seen between the two groups in terms of overall and disease-free survival. ALND was associated with a significantly higher risk of developing lymphoedema both in the short term and long term. The results of the AMAROS study suggest that for patients with early breast cancer, axillary radiotherapy may offer a
Pre-Z0011
Post-Z0011
ALND (N = 89) (94 %)
No ALND (N = 6) (6 %)
p
ALND (N = 80) (71 %)
No ALND (N = 32) (29 %)
p
Mean age (years)
52.1
73.5
0.003
54.7
63.2
\0.001
Mean tumour size (mm)
31.9
29.1
0.0016
31.0
26.3
\0.001
ER positive
82 (92.1 %)
6 (100 %)
0.4751
73 (91.3 %)
30 (93.8 %)
0.6629
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less radical alternative to ALND and its associated morbidity [20]. Despite the controversy surrounding Z0011, this study has been described as ‘‘practice changing’’ by authors who believe that it may dramatically change surgical management of the axilla [21, 22]. In this study, we demonstrated a 22.3 % decrease in the rate of ALND in all patients with positive SLNB and 26.7 % reduction in patients who would have been deemed eligible for Z0011 following the publication of the trial. This change in practice has occurred despite the lack of an official change in practice guidelines for surgeons in Ireland or the United Kingdom [11]. Previous investigators have explored the applicability of Z0011 in different patient cohorts [23–27]. Gu¨th et al. [23] carried out a retrospective analysis of patients undergoing SLNB in the setting of invasive breast cancer in order to identify the proportion of that would have been treated differently had the conclusions of Z0011 been applied. The investigators found that 9.0 % of patients in the study were eligible for inclusion in Z0011. This figure is significantly lower than the current study where 54.6 % of patients fit the Z0011 criteria. Gu¨th et al. demonstrated that a minimal number of patients in their cohort (0.5 %) would have been undertreated had the conclusions of Z0011 been applied and therefore no longer carry out ALND in the patients who fit the Z0011 criteria. However, as the application of the Z0011 findings would have changed management in only a small group of patients (9 % of all patients who underwent SLNB) the term ‘‘practice changing’’ should not be applied to this trial [28]. In a study by Ainsworth et al. (2013) the investigators noted that although Z0011 has important implications for patients with a positive SLNB, the overall impact of the trial is small due to the low numbers of patients in (6.9 %) who they found to be eligible for inclusion [24]. However, the patients that they deemed ‘eligible’ were taken as a proportion of the entire breast cancer cohort as opposed to examining them in the context of positive SLNB only. On examination of the patients with a positive findings on SLNB (n = 4,803) the majority (93.3 %, n = 4,482), fit the Z0011 criteria. Therefore, the impact of Z0011 on axillary practices in the SLNB positive patient may be higher than originally estimated. The results of this study show that there has been a reduction in the rate of ALND in sentinel lymph node positive patients since the publication of the ACOSOG Z0011 trial. The significant decrease from 93.7 % of positive SLNBs undergoing ALND pre-Z0011 to 71.4 % post-Z0011 represents a shift in the management of patients with axillary lymph node metastases. In our cohort of Z0011 eligible patients there was an even greater reduction in the rate of ALND was seen (92.3 % pre-Z0011
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to 65.5 % post-Z0011). These findings show that the conclusions of Z0011 are being applied not only to patients with similar disease burden to the Z0011 cohort, but also to patients who do not fit the eligibility criteria. This ‘blanket application’ of the Z0011 findings is not evidence based and may represent under-treatment of patients with more advanced disease. In addition, patients who did not undergo ALND in the post-Z0011 era were younger than the pre-Z0011 cohort. The omission of ALND in young patients with higher disease burden may increase the chance of locoregional recurrence and may ultimately decrease their overall survival. However, it is worth noting that in the post-Z0011 era, the patients proceeding to ALND were actually younger than those in the non-ALND group. This indicates that consideration is being given to prognostic factors when making decisions regarding ALND. Nevertheless, the application of the Z0011 findings to other cohorts of patients who were not specifically examined in Z0011 may be detrimental to patient outcomes. For example, subgroup analysis was not performed on patients with lobular carcinoma or those with the triple negative phenotype in Z0011. Furthermore, with the advent of the Oncotype DX breast cancer assay, patients with high recurrence scores warrant more careful consideration in a multidisciplinary setting before a decision is made to omit ALND. It would, therefore, be prudent to await data on these particular cohorts before applying Z0011 indiscriminately to all patients. Conversely, a reduction in the rate of ALND may be of benefit to the patient in terms of reduced morbidity as a result of lymphoedema [20]. In addition, a significant cost benefit may result from the reduction in ALND procedures with a recent study showing a 64 % reduction in inpatient hospital days and an 18 % reduction in perioperative costs [29]. Despite the potential benefits of a reduction in the rate of ALND, all decisions to undertake or omit ALND should be made on an individual basis in a multidisciplinary team setting. Current NICE guidelines warrant review in light of the Z0011 trial in order to clarify which patients are suitable for management according to the Z0011 protocol and to avoid under-treatment of patients who may benefit in the longer term from ALND. It is worth noting that the NCCN incorporated the results of Z0011 into their guidelines in 2011 and now recommend omission of ALND for patients meeting the entry criteria for Z0011 [30]. A similar change in guidelines should be considered by NICE. This study has demonstrated a practice change in the management of the axilla in Irish breast cancer patients. This change has been demonstrated in our cohort not only in patients who would have been eligible for inclusion in the ACOSOG Z0011 trial, but also in patients with higher disease burden. While the application of the Z0011 trial findings to patients who meet the criteria of the trial may be
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justified, patients who are to be spared from ALND based on the findings of Z0011 they should be required to satisfy the trial criteria. All decisions pertaining to this practice should be made in a multidisciplinary team setting in order to ensure optimal management of patients. In addition, we recommend that multidisciplinary guideline organisations such as NICE update their guidelines in view of these high profile and key new clinical trial findings. Conflict of interest
None.
References 1. Krag DN, Anderson SJ, Julian TB et al (2007) Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically nodenegative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol 8:881–888 2. Veronesi U, Paganelli G, Viale G et al (2003) A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 349:546–553 3. Fleissig A, Fallowfield LJ, Langridge CI et al (2006) Post-operative arm morbidity and quality of life: results of the ALMANAC randomised trial comparing sentinel node biopsy with standard axillary treatment in the management of patients with early breast cancer. Breast Cancer Res Treat 95:279–293 4. Lucci A, McCall LM, Beitsch PD et al (2007) Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol 25:3657–3663 5. Cyr A, Gillanders WE, Aft RL et al (2010) Micrometastatic disease and isolated tumor cells as a predictor for additional breast cancer axillary metastatic burden. Ann Surg Oncol 17(Suppl. 3):S303–S311 6. Cox CE, Kiluk VJ, Riker AI et al (2008) Significance of sentinel lymph node micrometastases in human breast cancer. J Am Coll Surg 206:261–268 7. Reed J, Rosman M, Verbanac KM et al (2009) Prognostic implications of isolated tumor cells and micrometastases in sentinel nodes of patients with invasive breast cancer: 10-year analysis of patients enrolled in the prospective East Carolina University/Anne Arundel Medical Center sentinel node multicenter study. J Am Coll Surg 208:333–340 8. De Boer M, van Deurzen C, van Dijck J et al (2009) Micrometastases or isolated tumor cells and the outcome of breast cancer. N Engl J Med 361:653–663 9. Truong PT, Vinh-Hung V, Cserni G et al (2008) The number of positive nodes and the ratio of positive to excised nodes are significant predictors of survival in women with micrometastatic node-positive breast cancer. Eur J Cancer 44:1670–1677 10. Colleoni M, Rotmensz N, Peruzzotti G et al (2005) Size of breast cancer metastases in axillary lymph nodes: clinical relevance of minimal lymph node involvement. J Clin Oncol 23:1379–1389 11. http://www.nice.org.uk/nicemedia/live/12132/43312/43312.pdf 12. Joyce DP, Solon JG, Prichard RS et al (2012) Is there a requirement for axillary lymph node dissection following identification of micro-metastasis or isolated tumour cells at sentinel node biopsy for breast cancer? Surgeon 10(6):326–329
13. Giuliano AE, McCall L, Beitsch P et al (2010) Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 252(3):426–432 14. Giuliano AE, Hunt KK, Ballman KV et al (2011) Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 305(6):569–575 15. Caudle AS, Hunt KK, Tucker SL et al (2012) American College of Surgeons Oncology Group (ACOSOG) Z0011: impact on surgeon practice patterns. Ann Surg Oncol 19(10):3144–3151 16. Giuliano AE, Kirgan DM, Guenther JM et al (1994) Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 220(3):391–401 17. Giuliano AE, Morrow M, Duggal S et al (2012) Should ACOSOG Z0011 change practice with respect to axillary lymph node dissection for a positive sentinel lymph node biopsy in breast cancer? Clin Exp Metastasis 29(7):687–692 18. Fisher B, Jeong JH, Anderson S et al (2002) Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347(8):567–575 19. Giuliano AE, Hawes D, Ballman KV et al (2011) Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA 306:385–393 20. Rutgers EJ, Donker M, Straver ME et al. (2013) Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: final analysis of the EORTC AMAROS trial. J Clin Oncol 31(suppl; abstr LBA 1001) 21. Caudle AS, Hunt KK, Kuerer HM et al (2011) Multidisciplinary considerations in the implementation of the findings from the American College of Surgeons Oncology Group (ACOSOG) Z0011 study: a practice-changing trial. Ann Surg Oncol 18:2407–2412 22. American Society of Clinical Oncology (ASCO). ASCO Perspective on JAMA breast cancer lymph node study findings. Available: http://www.racheldultz.com/ASCO.pdf 23. Gu¨th U, Myrick ME, Viehl CT et al (2012) The post ACOSOG Z0011 era: does our new understanding of breast cancer really change clinical practice? Eur J Surg Oncol 38(8):645–650 24. Olsen S, Amr B, Omar A et al (2011) Are the findings of ACOSOG Z0011 applicable to district general hospital unit—and how should they change our practice. Cancer Res 71:355s–356s 25. Lannin D, Killilea B, Grube B et al (2011) How generalizable is the patient population enrolled in ACOSOG Z0011? Cancer Res 71:366s–367s 26. Chalmers C, Mallon E, Stallard S et al (2011) The potential impact of applying the Z0011 trial to our practice in the UK. Cancer Res 71:368s 27. Yeow W, Thomee E, Roche N et al (2011) ACOSOG Z0011: are the results applicable to patients undergoing sentinel node biopsy in a UK breast unit. Eur J Surg Oncol 37:S11–S12 28. Ainsworth RK, Kollias J, Blanc AL et al (2013) The clinical impact of the American College of Surgeons Oncology Group Z-0011 trial—results from the BreastSurgANZ National Breast Cancer Audit. Breast 22(5):733–735 29. Camp MS, Greenup RA, Taghian A et al (2013) Application of ACOSOG Z0011 criteria reduces perioperative costs. Ann Surg Oncol 20(3):836–841 30. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
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ORIGINAL ARTICLE
Management of the axilla: has Z0011 had an impact? D. P. Joyce • A. J. Lowery • L. B. McGrath-Soo E. Downey • L. Kelly • G. T. O’Donoghue • M. Barry • A. D. K. Hill
•
Received: 10 April 2014 / Accepted: 31 December 2014 Ó Royal Academy of Medicine in Ireland 2015
Abstract Background Management of axillary disease in breast cancer has evolved significantly over the last two decades with the introduction of SLNB and a trend towards less radical surgery. Data from the American College of Surgeons Oncology Group Z0011 trial proposes that not all patients with positive axillary lymph nodes require completion axillary dissection. Aims The aim of this study was to determine whether there has been a change in practice patterns for axillary management in Ireland since the publication of this ‘practice-changing’ trial. Methods A review of breast cancers managed in the 12 months prior to publication of Z0011 (pre-Z0011) and comparison with those managed in the following 12 months (post-Z0011) was undertaken in three tertiary referral breast cancer centres. Patients with a positive SLNB were identified, and clinicopathologic data and subsequent management was compared between the two cohorts.
Results There were 708 SLNB performed during the study period; 326 pre-Z0011 and 382 post-Z0011. There was no difference in the rate of SLN positivity between the two cohorts: 29.1 % had a positive SLN pre-Z0011 and 29.3 % were positive post-Z0011. There were a significantly lower number of axillary clearances performed in SLN-positive patients in the post-Z0011 period (71.4 %) compared to the pre-Z011 period (93.7 %, p = 0.0022 Chi-square). Of the patients with tumour characteristics meeting the Z0011 inclusion criteria in the initial 12 months of the study, 92.3 % underwent ALND compared with 65.6 % in the final 12 months of the study (p = 0.0006 Chi-square). Conclusions There has been a change in clinical practice since the publication of the Z0011 trial, illustrated by a decrease in the rate of axillary clearance in node-positive breast cancers. Keywords Breast cancer Axilla Sentinel lymph node biopsy Axillary lymph node dissection ACOSOG Z0011
Introduction D. P. Joyce (&) A. J. Lowery L. B. McGrath-Soo E. Downey A. D. K. Hill Department of Breast and Endocrine Surgery, Beaumont Hospital, Dublin 9, Ireland e-mail: [email protected] L. Kelly Department of Breast Surgery, Cork University Hospital, Cork, Ireland G. T. O’Donoghue Department of Breast Surgery, Waterford Regional Hospital, Waterford, Ireland M. Barry Department of Breast Surgery, Mater Hospital, Dublin 7, Ireland
Management of the axilla in patients with breast cancer has evolved significantly in recent decades. The sentinel lymph node biopsy (SLNB) has become the standard of care for axillary staging in clinically node-negative patients [1, 2]. This procedure is associated with less short-term and longterm side effects than axillary lymph node dissection [3, 4]. Patients with a positive SLNB have been shown to be at risk of further axillary metastases, earlier disease recurrence and decreased overall survival. As a result, patients with a positive SLNB in the setting of breast cancer have traditionally been managed with axillary lymph node dissection (ALND) [5–10].
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Current NICE guidelines recommend that patients with early invasive breast cancer and either micrometastases or macrometastases on SLNB proceed to ALND [11]. Recent studies have suggested that patients with isolated tumour cells (ITCs) only identified at SLNB should be regarded as lymph node-negative and as such they can be spared ALND [11, 12]. However, the ACOSOG Z0011 trial proposes that not all patients with positive axillary lymph nodes identified at SLNB require completion ALND [13]. This trial was designed to determine whether ALND impacted on survival in selected SLN-positive breast cancer patients. Patients were randomised to either SLNB alone or SLNB followed by ALND. All patients were treated with wide local excision followed by breast irradiation. No difference in 5-year overall or disease-free survival was demonstrated between the two groups [14]. The authors concluded that SLNB alone does not result in inferior survival in patients with limited sentinel lymph node metastatic disease treated with WLE and systemic therapy compared to those treated with ALND [14]. The publication of this trial generated significant debate and discussion in the breast surgical oncology community leading to reports of changes in practice depending on institutional preferences [15]. This change in practice may be reasonable in the subset of patients who satisfy the ACOSOG Z0011 trial criteria; however, the omission of ALND in all patients with positive SLNBs is controversial. There has been no official change in guidance pertaining to the management of axillary disease by the National Cancer Control Programme (NCCP) in Ireland. The aim of this study was to determine the impact of Z0011 data on surgical practice and identify whether there has been a change in practice patterns for axillary management in an Irish population since the publication of the ACOSOG Z0011 trial.
Methods This study was carried out in three tertiary referral breast cancer centres: Beaumont Hospital (Dublin), Cork University Hospital, and Waterford Regional Hospital. In order to compare practices with regard to the management of the axilla pre- and post-publication of the ACOSOG Z0011 trial patients were divided into two groups according to the date of breast cancer treatment. The pre-Z0011 group, correspond to the group of patients who were treated in the 12 months prior to publication of the ACOSOG Z0011 trial (March 2010–February 2011). The post-Z0011 cohort includes patients who were treated in the 12 months following the publication of the Z0011 trial between March 2011 and February 2012. Data in each of the three participating centres were extracted from a prospectively maintained national database (Dendrite Clinical Systems
123
Ltd, Oxford, UK) in which clinical, radiological and pathological data are recorded for all patients attending triple assessment breast clinics. The outcome of multidisciplinary team discussion for any patients with breast pathology is also recorded prospectively in this database. Data obtained included patient demographics, age, gender, tumour size, number of positive sentinel lymph nodes and the size of sentinel lymph node metastases, and further axillary management. All sentinel lymph node biopsies were processed in a standardised fashion as follows: sentinel lymph nodes were measured and trimmed of fat; nodes were sectioned at 2 mm intervals perpendicular to the long axis; following overnight processing they were cut at three levels at 50 lm intervals for preparation of H&E stained sections; a spare section was cut at each level; Cytokeratin AE1/3 immunostain was performed on one of spare sections. Positive sentinel lymph nodes were defined as metastasis seen on standard H&E staining (as per the Z0011 criteria). Patients with ITC or metastasis seen only on immunohistochemistry were considered SLN negative. Data entry into the Dendrite database in each breast unit was performed by a dedicated data manager who had no interaction with patients and surgeons in order to ensure confidentiality and minimise bias in our dataset. Comparisons were made between groups using Chisquare for categorical variables and independent t test for means. Data analysis was performed using SPSS Version 12.
Results A total of 708 sentinel lymph node biopsies were performed during the 2-year period of the study. Three hundred and twenty-six were performed in the pre-Z0011 era and 382 in the 12 months following the publication of Z0011. There was no statistically significant difference in the rate of sentinel lymph node positivity between the two groups with 29.1 % (n = 95) of patients pre-Z0011 having a positive SNLB compared with 29.3 % (n = 112) postZ0011 (p = 1 Chi-square). A total of 89 patients (93.7 %) who had lymph node metastases identified on SLNB proceeded to ALND in the initial 12 months of the study. However, a significantly lower proportion underwent this procedure following the publication of Z0011 (n = 80, 71.4 %, p = 0.0022 Chisquare). Of the patients who had positive SLNB in the initial 12 months of the study, 54.7 % (n = 52) fit the Z0011 eligibility criteria. Similarly 54.5 % (n = 61) of patients were Z0011 eligible in the final 12 months of the study. Examination of these subgroups identified a significant change in practice with respect to the axilla in patients who had a positive SLNB. In the first 12 months of the study 48
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of the 52 (92.3 %) patients who would have been eligible for inclusion in the ACOSOG Z0011 trial proceeded to completion lymph node dissection. However, the group of patients who were treated following the publication of the results of Z0011 had a statistically significantly lower rate of ALND with only 40 out of 61 patients (65.6 %) undergoing this procedure (p = 0.0006 Chi-square). Pre-Z0011 cohort The clinicopathologic data pertaining to patients in the preand post-Z0011 cohorts are outlined in Table 1. In the preZ0011 cohort, patients who did not undergo ALND were older than those who proceeded to ALND (mean 73.5 vs. 52.1 years, p = 0.0034). The clinical tumour size in the non-ALND group was smaller than that of the ALND group (mean tumour size 29.1 vs. 31.9 mm, p = 0.0016. There was no difference in the rates of oestrogen receptor (ER) positivity between the ALND and non-ALND groups (92.1 vs. 100 %, p = 0.4751). Post-Z0011 cohort In the post-Z0011 cohort, the mean age of patients undergoing ALND was younger than those who did not proceed to ALND (mean 54.7 vs. 63.2 years, p \ 0.00001). The mean tumour size in the non-ALND group was smaller than in the ALND group (mean 26.3 vs. 31.0 mm, respectively, p \ 0.00001). In terms of ER status, there was no difference in the rates of ER positivity between the two groups (91.3 % in the ALND vs. 93.8 % in the non-ALND group, p = 0.6629).
Discussion The use of SLNB as a method of staging the axilla in patients with invasive breast cancer has radically changed practice since its introduction in the 1990s [16]. Thus far, patients with a positive SLNB have proceeded to ALND, a procedure which is associated with significant morbidity including lymphoedema and reduced arm movement [17]. However, in recent years there has been a trend towards Table 1 Clinicopathologic features of SLN-positive patients who did and did not undergo ALND pre- and postZ0011
less radical surgery not only in terms of our management of the breast, but also with regard the axilla. The ACOSOG Z0011 trial was established to investigate if ALND may be avoided in patients with sentinel lymph node metastases. The study showed that SLNB alone without ALND resulted in lower rates of locoregional recurrence with 5-year disease-free survival (DFS) of 82.2 % in the ALND group compared with 83.9 % in the SLNB alone group. Similarly, the Z0011 trial showed no difference in 5-year overall survival (OS) between the two arms of the study (91.8 % in the ALND group versus 92.5 % in the SLNB alone group) [17]. The results of this trial have generated a significant amount of controversy mainly in relation to the early closure of the study, a point which the investigators explained by the slow recruitment of participants. Length of followup has also been highlighted as a potential area of weakness in this study. However, given that median time to axillary recurrences in both NSABP B-04 [18] and ACOSOG Z0010 [19] was less than the median follow-up of 6.3 years in Z0011, the authors were of the opinion that length of follow-up was sufficient to identify the majority of axillary recurrences [17]. Some critics of Z0011 have highlighted that the majority of patients were postmenopausal and had ER-positive tumours and therefore questioned the validity of the study findings in the setting of premenopausal patients with ER-negative breast cancer. However, additional analysis of the patients included in the Z0011 trial showed no difference in outcomes between the two arms of the study for either premenopausal women or those with ER-negative tumours [17]. Similarly the EORTC AMAROS trial was established to investigate if axillary radiotherapy may offer a comparable alternative to ALND in cases of a positive SLNB. Patients included in this study were those with clinically nodenegative breast cancer. Patients in the axillary radiotherapy group were found to have similar axillary recurrence rates compared to the ALND group (1.03 vs. 0.54 %). Furthermore, no significant differences were seen between the two groups in terms of overall and disease-free survival. ALND was associated with a significantly higher risk of developing lymphoedema both in the short term and long term. The results of the AMAROS study suggest that for patients with early breast cancer, axillary radiotherapy may offer a
Pre-Z0011
Post-Z0011
ALND (N = 89) (94 %)
No ALND (N = 6) (6 %)
p
ALND (N = 80) (71 %)
No ALND (N = 32) (29 %)
p
Mean age (years)
52.1
73.5
0.003
54.7
63.2
\0.001
Mean tumour size (mm)
31.9
29.1
0.0016
31.0
26.3
\0.001
ER positive
82 (92.1 %)
6 (100 %)
0.4751
73 (91.3 %)
30 (93.8 %)
0.6629
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less radical alternative to ALND and its associated morbidity [20]. Despite the controversy surrounding Z0011, this study has been described as ‘‘practice changing’’ by authors who believe that it may dramatically change surgical management of the axilla [21, 22]. In this study, we demonstrated a 22.3 % decrease in the rate of ALND in all patients with positive SLNB and 26.7 % reduction in patients who would have been deemed eligible for Z0011 following the publication of the trial. This change in practice has occurred despite the lack of an official change in practice guidelines for surgeons in Ireland or the United Kingdom [11]. Previous investigators have explored the applicability of Z0011 in different patient cohorts [23–27]. Gu¨th et al. [23] carried out a retrospective analysis of patients undergoing SLNB in the setting of invasive breast cancer in order to identify the proportion of that would have been treated differently had the conclusions of Z0011 been applied. The investigators found that 9.0 % of patients in the study were eligible for inclusion in Z0011. This figure is significantly lower than the current study where 54.6 % of patients fit the Z0011 criteria. Gu¨th et al. demonstrated that a minimal number of patients in their cohort (0.5 %) would have been undertreated had the conclusions of Z0011 been applied and therefore no longer carry out ALND in the patients who fit the Z0011 criteria. However, as the application of the Z0011 findings would have changed management in only a small group of patients (9 % of all patients who underwent SLNB) the term ‘‘practice changing’’ should not be applied to this trial [28]. In a study by Ainsworth et al. (2013) the investigators noted that although Z0011 has important implications for patients with a positive SLNB, the overall impact of the trial is small due to the low numbers of patients in (6.9 %) who they found to be eligible for inclusion [24]. However, the patients that they deemed ‘eligible’ were taken as a proportion of the entire breast cancer cohort as opposed to examining them in the context of positive SLNB only. On examination of the patients with a positive findings on SLNB (n = 4,803) the majority (93.3 %, n = 4,482), fit the Z0011 criteria. Therefore, the impact of Z0011 on axillary practices in the SLNB positive patient may be higher than originally estimated. The results of this study show that there has been a reduction in the rate of ALND in sentinel lymph node positive patients since the publication of the ACOSOG Z0011 trial. The significant decrease from 93.7 % of positive SLNBs undergoing ALND pre-Z0011 to 71.4 % post-Z0011 represents a shift in the management of patients with axillary lymph node metastases. In our cohort of Z0011 eligible patients there was an even greater reduction in the rate of ALND was seen (92.3 % pre-Z0011
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to 65.5 % post-Z0011). These findings show that the conclusions of Z0011 are being applied not only to patients with similar disease burden to the Z0011 cohort, but also to patients who do not fit the eligibility criteria. This ‘blanket application’ of the Z0011 findings is not evidence based and may represent under-treatment of patients with more advanced disease. In addition, patients who did not undergo ALND in the post-Z0011 era were younger than the pre-Z0011 cohort. The omission of ALND in young patients with higher disease burden may increase the chance of locoregional recurrence and may ultimately decrease their overall survival. However, it is worth noting that in the post-Z0011 era, the patients proceeding to ALND were actually younger than those in the non-ALND group. This indicates that consideration is being given to prognostic factors when making decisions regarding ALND. Nevertheless, the application of the Z0011 findings to other cohorts of patients who were not specifically examined in Z0011 may be detrimental to patient outcomes. For example, subgroup analysis was not performed on patients with lobular carcinoma or those with the triple negative phenotype in Z0011. Furthermore, with the advent of the Oncotype DX breast cancer assay, patients with high recurrence scores warrant more careful consideration in a multidisciplinary setting before a decision is made to omit ALND. It would, therefore, be prudent to await data on these particular cohorts before applying Z0011 indiscriminately to all patients. Conversely, a reduction in the rate of ALND may be of benefit to the patient in terms of reduced morbidity as a result of lymphoedema [20]. In addition, a significant cost benefit may result from the reduction in ALND procedures with a recent study showing a 64 % reduction in inpatient hospital days and an 18 % reduction in perioperative costs [29]. Despite the potential benefits of a reduction in the rate of ALND, all decisions to undertake or omit ALND should be made on an individual basis in a multidisciplinary team setting. Current NICE guidelines warrant review in light of the Z0011 trial in order to clarify which patients are suitable for management according to the Z0011 protocol and to avoid under-treatment of patients who may benefit in the longer term from ALND. It is worth noting that the NCCN incorporated the results of Z0011 into their guidelines in 2011 and now recommend omission of ALND for patients meeting the entry criteria for Z0011 [30]. A similar change in guidelines should be considered by NICE. This study has demonstrated a practice change in the management of the axilla in Irish breast cancer patients. This change has been demonstrated in our cohort not only in patients who would have been eligible for inclusion in the ACOSOG Z0011 trial, but also in patients with higher disease burden. While the application of the Z0011 trial findings to patients who meet the criteria of the trial may be
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justified, patients who are to be spared from ALND based on the findings of Z0011 they should be required to satisfy the trial criteria. All decisions pertaining to this practice should be made in a multidisciplinary team setting in order to ensure optimal management of patients. In addition, we recommend that multidisciplinary guideline organisations such as NICE update their guidelines in view of these high profile and key new clinical trial findings. Conflict of interest
None.
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