- Email: [email protected]
Axillary recurrence in breast cancer
EJSO (2005) 31, 226–231
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Axillary recurrence in breast cancer D.B. Kingsmorea, D.J. Holeb,*, C.R. Gillisb, W.D. Georgea a
The University Department of Surgery, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK Public Health and Health Policy, The University of Glasgow, 1 Lilybank Gardens, Glasgow G12 8RZ, UK
b
Accepted for publication 9 December 2004 Available online 21 January 2005
KEYWORDS Axilla; Breast cancer; Recurrence
Abstract Aim. To determine whether axillary recurrence reflects inadequate axillary treatment or adverse pathological features. Methods. The case-records were reviewed of 2122 women aged under 75 years, treated for invasive breast cancer during the time-period 1/1/86–31/12/91 in a geographically defined area. Data were abstracted on operations performed, pathological features, post-operative treatments and details of axillary recurrence. The risk of axillary recurrence was examined by pathological, treatment and patient factors. Results. Axillary recurrence was more than twice as likely after inadequate compared to adequate treatment of the axilla (adequate staging or axillary radiotherapy or clearance). Delayed treatment of the axilla was not as successful as adequate primary treatment: multiple axillary recurrences were twice as common, one third of which were uncontrolled at time of death. Inadequate surgical treatment was associated with increased rates of recurrence despite endocrine therapy, chemotherapy or radiotherapy. Lymphoedema was twice as common if axillary radiotherapy was combined with any axillary surgical procedure. Conclusions. Axillary recurrence is more common in tumours with adverse pathology but may also result from inadequate axillary treatment. In order to minimise axillary recurrence, optimal treatment of the axilla entails adequate staging (sampling of four or more nodes) and treatment (axillary clearance or radiotherapy and endocrine therapy) in all women. q 2004 Elsevier Ltd. All rights reserved.
Introduction The necessity and practice of axillary surgery in women with breast cancer is controversial.1,2 The morbidity associated with axillary surgery must be balanced against the need for accurate staging to
* Corresponding author. Tel.: C44 141 330 3281. E-mail address: [email protected] (D.J. Hole).
prescribe chemotherapy, treat axillary disease and minimise the risk of recurrence.3–7 However, the morbidity from surgical staging may exceed any therapeutic benefit for women with small screendetected, well-differentiated tumours. Sentinel lymph node biopsy has been promoted as a method of axillary staging with minimal morbidity in these women, although there is concern over the potential risk of understaging with this technique.8 In addition, adjuvant chemotherapy is increasingly
0748-7983/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2004.12.003
Adequacy of axillary treatment and recurrence prescribed on the basis of tumour pathology. The long-term risks of selective axillary treatment are unclear, particularly for women with very small cancers. Thus, there has been considerable variability in the treatment of the axilla. The aim of this study was to determine the relative contribution of treatment variability and tumour pathology to axillary recurrence.
Methods Patients and data All women aged under 75 years who had been operated on for invasive breast cancer during the time-period 1/1/86–31/12/91, in a geographically defined area in the West of Scotland were identified through the West of Scotland Cancer Registry. The original pathology reports were reviewed and the following details obtained: tumour size, histological type, grade, number of axillary nodes removed, and number of positive axillary nodes. Oestrogen receptor status was not included in the analysis, as it was not routinely performed during the earlier part of this time-period. Data was incomplete on tumour type (not specified in 11 women), tumour size (missing in 204 women), and nodal status (unknown in 317 women in whom no axillary procedure was performed, not specified number of nodes examined in 164). All available caserecords were then obtained (2411), and if these were not available, the records from the regional centre for oncology were reviewed (350). All radiotherapy and chemotherapy were prescribed at the regional centre. The following data were abstracted: menopausal status, operations performed, pathological details (tumour size, nodal status, histological grade), post-operative treatments (radiotherapy, chemotherapy, endocrine therapy) and details of axillary recurrence. Standard six-cycle CMF chemotherapy was prescribed in the regional oncology centre. Axillary radiotherapy was delivered in a standard regimen with a total dose of 46 Gy to the axilla. No routine method of assessing lymphoedema was in use during this timeperiod. Significant lymphoedema has been empirically based on objective persistent arm swelling noted by the treating clinician at least 1 year after completion of axillary treatment requiring further treatment, such as a compression sleeve. Axillary recurrence was based on pathological confirmation of recurrence, or symptoms and undisputed clinical evidence of recurrence, before the appearance of other local or distant metastasis. The method of
227 detection of recurrence (symptomatic vs routine surveillance) was obtained from clinic letters. Time to recurrence was calculated from the date of operation. Two thousand nine hundred and twenty-eight women were registered as having a histologically verified invasive breast cancer. The records of 2761 (94%) women were reviewed. The cohort in this study consisted of 2122 women, treated with potentially curative surgery. Women with locally advanced inoperable tumours or metastatic disease were excluded. The median follow-up was 8 years, and 67 women lost to follow-up were censored at the date of last clinical review. Histological grading was not reported in all hospitals during the time-period of this study. Therefore, tumours were classified into histological prognostic groups based on type and grade where mentioned: good prognosis (ductal grade I, well differentiated and special types e.g. tubular), moderate prognosis (ductal grade II, no comment, or lobular), and poor prognosis (poorly differentiated or ductal grade III). Multivariate analysis of recurrence and survival confirmed this grouping as a valid predictor, independent of tumour size and nodal status.
Analysis Three treatment factors were considered important in terms of influencing axillary recurrence: the type of operative procedure, the adequacy of the operative procedure, and the use of axillary radiotherapy. The number of axillary nodes reported was taken as a crude marker of the adequacy of staging although this reflects both surgical thoroughness and pathological diligence. The recurrence rates of women with differing treatment strategies were compared by treatment (axillary clearance, sampling, radiotherapy), number of nodes reported and nodal status. Similarly effective treatments were combined to give a definition of adequate axillary treatment. The overall impact of inadequate compared to adequate axillary treatment on axillary recurrence was determined. Secondly, the risk of axillary recurrence was examined using univariate analysis of various factors: pathological factors (nodal status, tumour size, grade), other treatments (chemotherapy, endocrine therapy) and patient factors (menopausal status). A stepwise multivariate analysis of all factors that influenced axillary recurrence was performed. Finally, the risk of recurrence was examined in women with good prognostic tumours
228 (grade I, sized less than 10 mm) by adequacy of axillary treatment. Actuarial rates of axillary recurrence were calculated using life-tables. All distant and local recurrences were considered intercurrent events and censored at that time from further analysis. Cox’s proportional hazards model was used to estimate relative hazard ratios having adjusted for prognostic factors of menopausal status, tumour size, tumour grade, nodal status, adequacy of definitive axillary treatment and adjuvant therapy (chemotherapy, axillary radiotherapy, endocrine therapy).9
Results Patients The median age at diagnosis was 58 years (range 25– 74 years). Surgery for the primary tumour involved mastectomy in 52% and breast conservation in 48% of patients. The treatment of the axilla varied widely. Axillary surgery was performed in 1805 women (85%): axillary clearance in 1178 (56%), axillary sampling in 627 (29%), and no procedure in 317 women (15%). Axillary radiotherapy was given to 44% of women overall (926/2122); to 40% of woman who had an axillary clearance performed (477/1178), to 52% of women who had an axillary sample (328/627), and to 38% of women in whom no axillary surgery was performed (121/317). Adjuvant systemic therapy was prescribed to 80% of women (1688/2122): chemotherapy (131 women), endocrine therapy (1519 women), or both (38 women).
Presentation and time to axillary recurrence The first site of recurrence was the axilla in 7% (149/2122) of women, the majority of which presented symptomatically (117/146, 80%), with only 20% being detected on routine review. The median time to development of axillary recurrence was 37 months (range 1.6–128.5 months). Axillary recurrence was treated variably: surgery alone (30%), endocrine therapy alone (29%), radiotherapy alone (17%), and multimodality treatment (24%).
Incidence of axillary recurrence correlated with clinical and treatment variables The axillary recurrence rate was significantly lower after axillary clearance compared to other procedures (clearance 4%, sampling 10%, no procedure 13%, p!0.001), and lower in node negative compared to node positive women (5 vs 14%, p!0.001).
D.B. Kingsmore et al. Axillary clearance had a significantly lower recurrence rate than sampling, for both node negative (clearance 2% vs sampling 7%, p!0.001) and node positive women (6 vs 23%, p!0.001, Table 1). The recurrence rates after an axillary clearance was non-significantly higher if less than four nodes were removed (node negative 2 vs 5%; node positive 5 vs 8% pZNS, Table 1). The recurrence rate was not significantly different between axillary clearance and any procedure plus radiotherapy (node negative 2 vs 3%, node positive 6 vs 8%, pZNS). Axillary sampling of less than four negative nodes had a significantly higher rate of axillary recurrence compared to women who had an axillary clearance (9 vs 2%, p!0.001, RHRZ4.89, 2.13–11.1). The axillary recurrence rate for women in whom four or more nodes were removed was of borderline significance when compared to women who had an axillary clearance (5 vs 2%, pZ0.052, RHRZ2.53, 0.96–6.65). In node positive women in whom only a sampling procedure was performed, the overall axillary recurrence rate was four times higher than for women in whom a clearance was performed (23 vs 6%, p!0.001), and three times higher than for women who also received radiotherapy (23 vs 8%, p!0.001). Adequate axillary treatment was thus defined as axillary clearance, adequate negative staging (axillary clearance or sample of 4 or more negative nodes), and any procedure with radiotherapy. The overall risk of axillary recurrence associated with inadequate axillary treatment was higher for both node negative (5-year recurrence rates: adequate 2% vs inadequate 8%, RHRZ4.34, 2.14–8.82, p! 0.001, Table 2) and node positive women (5-year recurrence rates: adequate 13% vs inadequate 21%, RHRZ1.89, 1.27–2.80, p!0.01). Menopausal status did not affect the increased axillary recurrence rate due to inadequate axillary treatment—five times higher in pre-menopausal women (3 vs 15%, p!0.001), and three times higher in post-menopausal women (5 vs 13%, p!0.001). Pre-menopausal women were prescribed chemotherapy twice as frequently if axillary treatment was ‘adequate’ compared to women with ‘inadequate’ axillary treatment (114/423, 27% vs 22/141, 16%, p!0.001). The addition of chemotherapy in pre-menopausal women did not influence axillary recurrence rates in those with adequate axillary treatment (3 vs 3%, pZNS) or those with inadequate axillary treatment (20 vs 14%, pZNS). Endocrine therapy was prescribed to 80% of postmenopausal women irrelevant of axillary nodal status or the adequacy of axillary treatment. In
Adequacy of axillary treatment and recurrence Table 1
229
The axillary recurrence rate by type of axillary procedure, number of nodes removed and nodal status
Axillary procedure Node negative women Sample only Clearance only Sample or clearance and RT Node positive women Sample only Clearance only Sample or clearance and RT
Number of nodes removed Unknown 1–3
4C
Total
2/44, 4% 1/37, 3% 1/37, 3%
10/107, 9% 2/42, 5% 1/39, 3%
6/112, 5% 9/532, 2% 1/40, 2%
18/263, 7% 12/611, 2% 3/116, 3%
3/15, 20% 2/9, 22% 3/29, 10%
8/24, 33% 1/13, 8% 5/62, 8%
15/75, 20% 22/415, 5% 11/140, 8%
26/114, 23% 25/437, 6% 19/231, 8%
post-menopausal women with adequate axillary treatment, the addition of endocrine therapy significantly decreased the axillary recurrence rate (overall: 8 vs 4%, pZ0.002; node negative: 7 vs 2%, p!0.001; node positive: 11 vs 6%, p!0.001). However, in women with inadequate axillary treatment, the addition of endocrine therapy did not influence axillary recurrence rate (node negative: 10 vs 8%, pZNS; node positive women: 21 vs 18%, pZNS).
significant independent factors on multivariate analysis (Table 3). The axillary recurrence rate in women with grade I tumours smaller than 10 mm was higher if treatment was inadequate compared to adequate (9 vs 3%), although this was not significant due to the small numbers involved. The risk of axillary recurrence was significantly higher in women with four or more positive nodes if axillary treatment was inadequate (46 vs 7%, p!0.001).
The risk of axillary recurrence
The incidence of complications by type of axillary treatment
The risk of axillary recurrence on univariate analysis was examined in relation to patient, pathological and treatment factors (Table 3). There was no association between recurrence and menopausal status. However, the following pathological factors were significantly associated: tumour size, nodal status and grade. Adequacy of axillary treatment, grade, nodal status and tumour size remained as Table 2 Axillary recurrence rate by nodal status and adequacy of axillary treatment Nodal status
Negative Incidence 5 year rate Positive Incidence 5 year rate Total a b c
Adequacy of axillary treatment Adequate Inadequate RHRa (95% CI) 29/944 2%
44/403 8%
37/612 13%
36/188 21%
4%
14%
The incidence of lymphoedema was similar in women treated with sampling only (20/416, 5%), clearance only (69/1099, 6%) or axillary radiotherapy only (4/92, 4%). However, the addition of radiotherapy to either of the operative procedures doubled the incidence of lymphoedema (26/230, 11% for sampling, 17/123, 14% for clearance, p! 0.001). Multiple axillary recurrences were more often seen in inadequately treated women (18 vs 7%, p! 0.001). In addition, uncontrolled axillary recurrence occurred in one third of these women whose axillary treatment was ‘inadequate’ and developed a recurrence. No woman who received adequate axillary treatment had an uncontrolled recurrence.
4.34b (2.14–8.82)
Discussion 1.89c (1.27–2.80) 2.10b (1.53–2.88)
After adjustment for nodal status, grade and tumour size. p!0.001. p!0.01.
The merits of routine axillary surgery have been debated extensively for the past two decades. We have used the ensuing wide variability in axillary treatment to determine the impact of these regimens on recurrence, with the aim of determining if a selective policy of axillary treatment could be justified. Our results show that axillary recurrence
230
D.B. Kingsmore et al.
Table 3 The relative hazard ratio of axillary recurrence by patient, pathological and treatment factors on univariate and multivariate analysis Factor Pathological factors Tumour size !20 mm 20–39 mm 40Cmm Nodal status Node negative Node positive Grade Grade I Grade II Grade III Operative factors Number nodes 4CNodes 1–3 Nodes Axillary procedure Axillary clearance Axillary sampling No procedure
Univariate RHR (95% CI)
Multivariate RHRa (95% CI)
1.00 2.31b (1.53–3.48) 5.11b (3.27–8.00)
1.59c (1.16–2.14)
1.00 1.49d (1.03–2.16)
2.08b (1.56–2.70)
1.00 3.90c (1.51–10.0) 9.92b (3.98–24.7)
1.99b (1.32–2.97)
1.00 1.79c (1.22–2.63) 1.00 1.61c (1.16–2.25) 1.69d (1.13–2.53)
Adequacy of treatment Adequate 1.00 Inadequate 2.28b (1.69–3.06)
1.47b (1.24–1.74)
a
After adjustment for tumour size, grade, and nodal status where appropriate. b p!0.001. c p!0.01. d p!0.05.
is always higher after inadequate treatment, irrespective of the use of adjuvant therapy. The retrospective audit of case-records was not subject to selection bias as all women identified with breast cancer over a 6 year period in a geographical area were included. The accuracy of the data obtained was confirmed by obtaining data from two separate sources independently—the pathology reports and subsequently the caserecords. The validity of our data set was confirmed by both ensuring internal consistency (confirming that established predictive variables of size, grade, nodal status correlated with axillary recurrence rates), and by ensuring that our results were
consistent with randomised trials and other series. Thus we are confident that the data analysed were accurate and complete. Our definition of adequacy of axillary treatment is based on the subjective description of the surgical procedure performed and the objective pathological analysis of the specimen. The difficulty of definition of surgical procedure has been highlighted.10–12 We found that the description of procedure performed varied considerably, and potentially this could have led to misclassification of the operation. However, the recurrence rates in the few women who had a small number of nodes removed by a ‘clearance’ were lower than women who had a similar number of nodes removed by axillary sampling. Thus, the classification of adequacy discriminated those women who had adequate treatment from those who did not. Wide variability in the thoroughness of axillary treatment was found: from 10% in whom no staging or treatment was performed, to 22% of women who received radiotherapy after an axillary clearance. Adequacy of axillary surgery has rarely been correlated with the procedure performed. A previous study in England found higher rates of axillary recurrence with axillary sampling compared to clearance (recurrence rates of 8 and 3% in node negative women, and 12 and 3% in node positive women).13 This may reflect the vigour of node retrieval, as axillary sampling has been shown to accurately stage the axilla in specialised units4,14 and higher recurrence rates are found in node negative women when less than five nodes are removed.15,16 We found that one third of all sampling procedures resulted in inadequate node retrieval (less than four nodes removed). The extent to which this reflects the thoroughness of the operative procedure or examining pathologist is uncertain. Despite this, the adequacy of axillary treatment remained a significant variable in predicting the axillary recurrence rate after allowing for the pathological characteristics of the primary tumour. We could not identify a subgroup of women (on the basis of age, menopausal status, tumour pathology and adjuvant treatment) in whom axillary treatment could be omitted without increasing the risk of axillary recurrence. Whilst endocrine therapy halved the rate of axillary recurrence in women in whom the axillary treatment was adequate, it could not compensate for inadequate surgery. Multiple and uncontrolled axillary recurrences were only found in women in whom the initial treatment was inadequate. Delayed axillary treatment did not appear to be as successful in treating the axilla as adequate primary treatment. The performance of routine axillary staging
Adequacy of axillary treatment and recurrence remains controversial. The morbidity associated with axillary clearance has led to the development of less invasive procedures including sentinel node biopsy, to identify node negative women who do not require further axillary treatment. In minimising the 5% morbidity associated with more extensive surgery, there is a risk of misclassifying node positive women, under-treating the axilla, depriving them of adjuvant chemotherapy, not employing endocrine therapy in the most advantageous setting and allowing regional and systemic recurrence. Whilst many factors influencing axillary recurrence are outwith the control of treating physicians, the adequacy of axillary treatment and the use of endocrine therapy are not. We believe that whilst axillary failure is more common in tumours with adverse pathology, it also reflects inadequate definitive axillary treatment. In order to minimise axillary recurrence, optimal treatment of the axilla entails axillary clearance or sampling of four or more nodes with the selective use of radiotherapy and endocrine therapy in all women.
References 1. Fentiman IS, Mansel RE. The axilla: not a no-go zone. Lancet 1991;337:221–3. 2. Morrow M. Axillary dissection: when and how radical? Semin Surg Oncol 1996;12:321–7. 3. Greenall MJ. Current controversies in the surgical management of breast cancer. Ann Oncol 1994;5:S39–S43. 4. Greenall MJ. How should the axilla be treated in breast cancer? Why I favour axillary node sampling in the management of breast cancer Eur J Surg Oncol 1995;21:2–5.
231 5. Moore GE, Abernathy C. Axillary dissection in breast cancer. Lancet 1991;337:487–8. 6. Davidson T. How should the axilla be treated in breast cancer? Why I favour axillary node clearance in the management of breast cancer Eur J Surg Oncol 1995;21:5–7. 7. Evans RA. Rationale for routine axillary dissection in carcinoma of the breast. J Am Coll Surg 1996;182:277–8. 8. Hansen NM, Grube BJ, Giuliano AE. The time has come to change the algorithm for the surgical management of early breast cancer. Arch Surg 2002;137:1131–5. 9. Cox DR. Regression models and life-tables. J R Stat Soc 1972; 34:187–220. 10. Christiaens MR. Documentation of the surgical procedure: a tool for quality assessment for breast conservative treatment. Anticancer Res 1996;16:3955–8. 11. Christiaens MR, Cataliotti L, Fentiman I, Rutgers E, BlichertToft M, DeVries JE, et al. Comparison of the surgical procedures for breast conserving treatment of early breast cancer in seven EORTC centres. Eur J Cancer 1996;32: 1866–75. 12. Fentiman IS. Quality control in breast cancer treatment: what information can the surgeon provide? Radiother Oncol 1991;22:226–9. 13. Benson EA, Thoroughgood J. The effect of surgical technique on local recurrence rates following mastectomy. Eur J Surg Oncol 1986;12:267–71. 14. Forrest AP, Everington D, McDonald CC, Steele RJ, Chetty U, Stewart HJ. The Edinburgh randomized trial of axillary sampling or clearance after mastectomy. Br J Surg 1995;82: 1504–8. 15. Graversen HP, Blichert-Toft M, Andersen JA, Zedeler K. Breast cancer: the risk of axillary recurrence in nodenegative patients following partial dissection of the axilla. Eur J Surg Oncol 1988;14:407–12. 16. Axelsson CK, Mouridsen HT, Zedeler K. Axillary disection of level I and II lymph nodes is important in breast cancer classification. The Danish Breast Cancer Cooperative Group (DBCG). Eur J Cancer 1992;28A:1415–8.
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Axillary recurrence in breast cancer D.B. Kingsmorea, D.J. Holeb,*, C.R. Gillisb, W.D. Georgea a
The University Department of Surgery, Western Infirmary, Dumbarton Road, Glasgow G11 6NT, UK Public Health and Health Policy, The University of Glasgow, 1 Lilybank Gardens, Glasgow G12 8RZ, UK
b
Accepted for publication 9 December 2004 Available online 21 January 2005
KEYWORDS Axilla; Breast cancer; Recurrence
Abstract Aim. To determine whether axillary recurrence reflects inadequate axillary treatment or adverse pathological features. Methods. The case-records were reviewed of 2122 women aged under 75 years, treated for invasive breast cancer during the time-period 1/1/86–31/12/91 in a geographically defined area. Data were abstracted on operations performed, pathological features, post-operative treatments and details of axillary recurrence. The risk of axillary recurrence was examined by pathological, treatment and patient factors. Results. Axillary recurrence was more than twice as likely after inadequate compared to adequate treatment of the axilla (adequate staging or axillary radiotherapy or clearance). Delayed treatment of the axilla was not as successful as adequate primary treatment: multiple axillary recurrences were twice as common, one third of which were uncontrolled at time of death. Inadequate surgical treatment was associated with increased rates of recurrence despite endocrine therapy, chemotherapy or radiotherapy. Lymphoedema was twice as common if axillary radiotherapy was combined with any axillary surgical procedure. Conclusions. Axillary recurrence is more common in tumours with adverse pathology but may also result from inadequate axillary treatment. In order to minimise axillary recurrence, optimal treatment of the axilla entails adequate staging (sampling of four or more nodes) and treatment (axillary clearance or radiotherapy and endocrine therapy) in all women. q 2004 Elsevier Ltd. All rights reserved.
Introduction The necessity and practice of axillary surgery in women with breast cancer is controversial.1,2 The morbidity associated with axillary surgery must be balanced against the need for accurate staging to
* Corresponding author. Tel.: C44 141 330 3281. E-mail address: [email protected] (D.J. Hole).
prescribe chemotherapy, treat axillary disease and minimise the risk of recurrence.3–7 However, the morbidity from surgical staging may exceed any therapeutic benefit for women with small screendetected, well-differentiated tumours. Sentinel lymph node biopsy has been promoted as a method of axillary staging with minimal morbidity in these women, although there is concern over the potential risk of understaging with this technique.8 In addition, adjuvant chemotherapy is increasingly
0748-7983/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2004.12.003
Adequacy of axillary treatment and recurrence prescribed on the basis of tumour pathology. The long-term risks of selective axillary treatment are unclear, particularly for women with very small cancers. Thus, there has been considerable variability in the treatment of the axilla. The aim of this study was to determine the relative contribution of treatment variability and tumour pathology to axillary recurrence.
Methods Patients and data All women aged under 75 years who had been operated on for invasive breast cancer during the time-period 1/1/86–31/12/91, in a geographically defined area in the West of Scotland were identified through the West of Scotland Cancer Registry. The original pathology reports were reviewed and the following details obtained: tumour size, histological type, grade, number of axillary nodes removed, and number of positive axillary nodes. Oestrogen receptor status was not included in the analysis, as it was not routinely performed during the earlier part of this time-period. Data was incomplete on tumour type (not specified in 11 women), tumour size (missing in 204 women), and nodal status (unknown in 317 women in whom no axillary procedure was performed, not specified number of nodes examined in 164). All available caserecords were then obtained (2411), and if these were not available, the records from the regional centre for oncology were reviewed (350). All radiotherapy and chemotherapy were prescribed at the regional centre. The following data were abstracted: menopausal status, operations performed, pathological details (tumour size, nodal status, histological grade), post-operative treatments (radiotherapy, chemotherapy, endocrine therapy) and details of axillary recurrence. Standard six-cycle CMF chemotherapy was prescribed in the regional oncology centre. Axillary radiotherapy was delivered in a standard regimen with a total dose of 46 Gy to the axilla. No routine method of assessing lymphoedema was in use during this timeperiod. Significant lymphoedema has been empirically based on objective persistent arm swelling noted by the treating clinician at least 1 year after completion of axillary treatment requiring further treatment, such as a compression sleeve. Axillary recurrence was based on pathological confirmation of recurrence, or symptoms and undisputed clinical evidence of recurrence, before the appearance of other local or distant metastasis. The method of
227 detection of recurrence (symptomatic vs routine surveillance) was obtained from clinic letters. Time to recurrence was calculated from the date of operation. Two thousand nine hundred and twenty-eight women were registered as having a histologically verified invasive breast cancer. The records of 2761 (94%) women were reviewed. The cohort in this study consisted of 2122 women, treated with potentially curative surgery. Women with locally advanced inoperable tumours or metastatic disease were excluded. The median follow-up was 8 years, and 67 women lost to follow-up were censored at the date of last clinical review. Histological grading was not reported in all hospitals during the time-period of this study. Therefore, tumours were classified into histological prognostic groups based on type and grade where mentioned: good prognosis (ductal grade I, well differentiated and special types e.g. tubular), moderate prognosis (ductal grade II, no comment, or lobular), and poor prognosis (poorly differentiated or ductal grade III). Multivariate analysis of recurrence and survival confirmed this grouping as a valid predictor, independent of tumour size and nodal status.
Analysis Three treatment factors were considered important in terms of influencing axillary recurrence: the type of operative procedure, the adequacy of the operative procedure, and the use of axillary radiotherapy. The number of axillary nodes reported was taken as a crude marker of the adequacy of staging although this reflects both surgical thoroughness and pathological diligence. The recurrence rates of women with differing treatment strategies were compared by treatment (axillary clearance, sampling, radiotherapy), number of nodes reported and nodal status. Similarly effective treatments were combined to give a definition of adequate axillary treatment. The overall impact of inadequate compared to adequate axillary treatment on axillary recurrence was determined. Secondly, the risk of axillary recurrence was examined using univariate analysis of various factors: pathological factors (nodal status, tumour size, grade), other treatments (chemotherapy, endocrine therapy) and patient factors (menopausal status). A stepwise multivariate analysis of all factors that influenced axillary recurrence was performed. Finally, the risk of recurrence was examined in women with good prognostic tumours
228 (grade I, sized less than 10 mm) by adequacy of axillary treatment. Actuarial rates of axillary recurrence were calculated using life-tables. All distant and local recurrences were considered intercurrent events and censored at that time from further analysis. Cox’s proportional hazards model was used to estimate relative hazard ratios having adjusted for prognostic factors of menopausal status, tumour size, tumour grade, nodal status, adequacy of definitive axillary treatment and adjuvant therapy (chemotherapy, axillary radiotherapy, endocrine therapy).9
Results Patients The median age at diagnosis was 58 years (range 25– 74 years). Surgery for the primary tumour involved mastectomy in 52% and breast conservation in 48% of patients. The treatment of the axilla varied widely. Axillary surgery was performed in 1805 women (85%): axillary clearance in 1178 (56%), axillary sampling in 627 (29%), and no procedure in 317 women (15%). Axillary radiotherapy was given to 44% of women overall (926/2122); to 40% of woman who had an axillary clearance performed (477/1178), to 52% of women who had an axillary sample (328/627), and to 38% of women in whom no axillary surgery was performed (121/317). Adjuvant systemic therapy was prescribed to 80% of women (1688/2122): chemotherapy (131 women), endocrine therapy (1519 women), or both (38 women).
Presentation and time to axillary recurrence The first site of recurrence was the axilla in 7% (149/2122) of women, the majority of which presented symptomatically (117/146, 80%), with only 20% being detected on routine review. The median time to development of axillary recurrence was 37 months (range 1.6–128.5 months). Axillary recurrence was treated variably: surgery alone (30%), endocrine therapy alone (29%), radiotherapy alone (17%), and multimodality treatment (24%).
Incidence of axillary recurrence correlated with clinical and treatment variables The axillary recurrence rate was significantly lower after axillary clearance compared to other procedures (clearance 4%, sampling 10%, no procedure 13%, p!0.001), and lower in node negative compared to node positive women (5 vs 14%, p!0.001).
D.B. Kingsmore et al. Axillary clearance had a significantly lower recurrence rate than sampling, for both node negative (clearance 2% vs sampling 7%, p!0.001) and node positive women (6 vs 23%, p!0.001, Table 1). The recurrence rates after an axillary clearance was non-significantly higher if less than four nodes were removed (node negative 2 vs 5%; node positive 5 vs 8% pZNS, Table 1). The recurrence rate was not significantly different between axillary clearance and any procedure plus radiotherapy (node negative 2 vs 3%, node positive 6 vs 8%, pZNS). Axillary sampling of less than four negative nodes had a significantly higher rate of axillary recurrence compared to women who had an axillary clearance (9 vs 2%, p!0.001, RHRZ4.89, 2.13–11.1). The axillary recurrence rate for women in whom four or more nodes were removed was of borderline significance when compared to women who had an axillary clearance (5 vs 2%, pZ0.052, RHRZ2.53, 0.96–6.65). In node positive women in whom only a sampling procedure was performed, the overall axillary recurrence rate was four times higher than for women in whom a clearance was performed (23 vs 6%, p!0.001), and three times higher than for women who also received radiotherapy (23 vs 8%, p!0.001). Adequate axillary treatment was thus defined as axillary clearance, adequate negative staging (axillary clearance or sample of 4 or more negative nodes), and any procedure with radiotherapy. The overall risk of axillary recurrence associated with inadequate axillary treatment was higher for both node negative (5-year recurrence rates: adequate 2% vs inadequate 8%, RHRZ4.34, 2.14–8.82, p! 0.001, Table 2) and node positive women (5-year recurrence rates: adequate 13% vs inadequate 21%, RHRZ1.89, 1.27–2.80, p!0.01). Menopausal status did not affect the increased axillary recurrence rate due to inadequate axillary treatment—five times higher in pre-menopausal women (3 vs 15%, p!0.001), and three times higher in post-menopausal women (5 vs 13%, p!0.001). Pre-menopausal women were prescribed chemotherapy twice as frequently if axillary treatment was ‘adequate’ compared to women with ‘inadequate’ axillary treatment (114/423, 27% vs 22/141, 16%, p!0.001). The addition of chemotherapy in pre-menopausal women did not influence axillary recurrence rates in those with adequate axillary treatment (3 vs 3%, pZNS) or those with inadequate axillary treatment (20 vs 14%, pZNS). Endocrine therapy was prescribed to 80% of postmenopausal women irrelevant of axillary nodal status or the adequacy of axillary treatment. In
Adequacy of axillary treatment and recurrence Table 1
229
The axillary recurrence rate by type of axillary procedure, number of nodes removed and nodal status
Axillary procedure Node negative women Sample only Clearance only Sample or clearance and RT Node positive women Sample only Clearance only Sample or clearance and RT
Number of nodes removed Unknown 1–3
4C
Total
2/44, 4% 1/37, 3% 1/37, 3%
10/107, 9% 2/42, 5% 1/39, 3%
6/112, 5% 9/532, 2% 1/40, 2%
18/263, 7% 12/611, 2% 3/116, 3%
3/15, 20% 2/9, 22% 3/29, 10%
8/24, 33% 1/13, 8% 5/62, 8%
15/75, 20% 22/415, 5% 11/140, 8%
26/114, 23% 25/437, 6% 19/231, 8%
post-menopausal women with adequate axillary treatment, the addition of endocrine therapy significantly decreased the axillary recurrence rate (overall: 8 vs 4%, pZ0.002; node negative: 7 vs 2%, p!0.001; node positive: 11 vs 6%, p!0.001). However, in women with inadequate axillary treatment, the addition of endocrine therapy did not influence axillary recurrence rate (node negative: 10 vs 8%, pZNS; node positive women: 21 vs 18%, pZNS).
significant independent factors on multivariate analysis (Table 3). The axillary recurrence rate in women with grade I tumours smaller than 10 mm was higher if treatment was inadequate compared to adequate (9 vs 3%), although this was not significant due to the small numbers involved. The risk of axillary recurrence was significantly higher in women with four or more positive nodes if axillary treatment was inadequate (46 vs 7%, p!0.001).
The risk of axillary recurrence
The incidence of complications by type of axillary treatment
The risk of axillary recurrence on univariate analysis was examined in relation to patient, pathological and treatment factors (Table 3). There was no association between recurrence and menopausal status. However, the following pathological factors were significantly associated: tumour size, nodal status and grade. Adequacy of axillary treatment, grade, nodal status and tumour size remained as Table 2 Axillary recurrence rate by nodal status and adequacy of axillary treatment Nodal status
Negative Incidence 5 year rate Positive Incidence 5 year rate Total a b c
Adequacy of axillary treatment Adequate Inadequate RHRa (95% CI) 29/944 2%
44/403 8%
37/612 13%
36/188 21%
4%
14%
The incidence of lymphoedema was similar in women treated with sampling only (20/416, 5%), clearance only (69/1099, 6%) or axillary radiotherapy only (4/92, 4%). However, the addition of radiotherapy to either of the operative procedures doubled the incidence of lymphoedema (26/230, 11% for sampling, 17/123, 14% for clearance, p! 0.001). Multiple axillary recurrences were more often seen in inadequately treated women (18 vs 7%, p! 0.001). In addition, uncontrolled axillary recurrence occurred in one third of these women whose axillary treatment was ‘inadequate’ and developed a recurrence. No woman who received adequate axillary treatment had an uncontrolled recurrence.
4.34b (2.14–8.82)
Discussion 1.89c (1.27–2.80) 2.10b (1.53–2.88)
After adjustment for nodal status, grade and tumour size. p!0.001. p!0.01.
The merits of routine axillary surgery have been debated extensively for the past two decades. We have used the ensuing wide variability in axillary treatment to determine the impact of these regimens on recurrence, with the aim of determining if a selective policy of axillary treatment could be justified. Our results show that axillary recurrence
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Table 3 The relative hazard ratio of axillary recurrence by patient, pathological and treatment factors on univariate and multivariate analysis Factor Pathological factors Tumour size !20 mm 20–39 mm 40Cmm Nodal status Node negative Node positive Grade Grade I Grade II Grade III Operative factors Number nodes 4CNodes 1–3 Nodes Axillary procedure Axillary clearance Axillary sampling No procedure
Univariate RHR (95% CI)
Multivariate RHRa (95% CI)
1.00 2.31b (1.53–3.48) 5.11b (3.27–8.00)
1.59c (1.16–2.14)
1.00 1.49d (1.03–2.16)
2.08b (1.56–2.70)
1.00 3.90c (1.51–10.0) 9.92b (3.98–24.7)
1.99b (1.32–2.97)
1.00 1.79c (1.22–2.63) 1.00 1.61c (1.16–2.25) 1.69d (1.13–2.53)
Adequacy of treatment Adequate 1.00 Inadequate 2.28b (1.69–3.06)
1.47b (1.24–1.74)
a
After adjustment for tumour size, grade, and nodal status where appropriate. b p!0.001. c p!0.01. d p!0.05.
is always higher after inadequate treatment, irrespective of the use of adjuvant therapy. The retrospective audit of case-records was not subject to selection bias as all women identified with breast cancer over a 6 year period in a geographical area were included. The accuracy of the data obtained was confirmed by obtaining data from two separate sources independently—the pathology reports and subsequently the caserecords. The validity of our data set was confirmed by both ensuring internal consistency (confirming that established predictive variables of size, grade, nodal status correlated with axillary recurrence rates), and by ensuring that our results were
consistent with randomised trials and other series. Thus we are confident that the data analysed were accurate and complete. Our definition of adequacy of axillary treatment is based on the subjective description of the surgical procedure performed and the objective pathological analysis of the specimen. The difficulty of definition of surgical procedure has been highlighted.10–12 We found that the description of procedure performed varied considerably, and potentially this could have led to misclassification of the operation. However, the recurrence rates in the few women who had a small number of nodes removed by a ‘clearance’ were lower than women who had a similar number of nodes removed by axillary sampling. Thus, the classification of adequacy discriminated those women who had adequate treatment from those who did not. Wide variability in the thoroughness of axillary treatment was found: from 10% in whom no staging or treatment was performed, to 22% of women who received radiotherapy after an axillary clearance. Adequacy of axillary surgery has rarely been correlated with the procedure performed. A previous study in England found higher rates of axillary recurrence with axillary sampling compared to clearance (recurrence rates of 8 and 3% in node negative women, and 12 and 3% in node positive women).13 This may reflect the vigour of node retrieval, as axillary sampling has been shown to accurately stage the axilla in specialised units4,14 and higher recurrence rates are found in node negative women when less than five nodes are removed.15,16 We found that one third of all sampling procedures resulted in inadequate node retrieval (less than four nodes removed). The extent to which this reflects the thoroughness of the operative procedure or examining pathologist is uncertain. Despite this, the adequacy of axillary treatment remained a significant variable in predicting the axillary recurrence rate after allowing for the pathological characteristics of the primary tumour. We could not identify a subgroup of women (on the basis of age, menopausal status, tumour pathology and adjuvant treatment) in whom axillary treatment could be omitted without increasing the risk of axillary recurrence. Whilst endocrine therapy halved the rate of axillary recurrence in women in whom the axillary treatment was adequate, it could not compensate for inadequate surgery. Multiple and uncontrolled axillary recurrences were only found in women in whom the initial treatment was inadequate. Delayed axillary treatment did not appear to be as successful in treating the axilla as adequate primary treatment. The performance of routine axillary staging
Adequacy of axillary treatment and recurrence remains controversial. The morbidity associated with axillary clearance has led to the development of less invasive procedures including sentinel node biopsy, to identify node negative women who do not require further axillary treatment. In minimising the 5% morbidity associated with more extensive surgery, there is a risk of misclassifying node positive women, under-treating the axilla, depriving them of adjuvant chemotherapy, not employing endocrine therapy in the most advantageous setting and allowing regional and systemic recurrence. Whilst many factors influencing axillary recurrence are outwith the control of treating physicians, the adequacy of axillary treatment and the use of endocrine therapy are not. We believe that whilst axillary failure is more common in tumours with adverse pathology, it also reflects inadequate definitive axillary treatment. In order to minimise axillary recurrence, optimal treatment of the axilla entails axillary clearance or sampling of four or more nodes with the selective use of radiotherapy and endocrine therapy in all women.
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