© 2007 European Society for Medical Oncology
breast cancer |
Is avoiding post-mastectomy radiotherapy justified for patients with four or more involved axillary nodes and endocrine-responsive tumours? Lessons from a series in a single institution
1 Division of Breast Surgery
2 Division of Epidemiology and Biostatistics
3 Department of Medical Oncology
4 Scientific Director, European Institute of Oncology, Milan, Italy
* Correspondence to: Dr O. Gentilini, Division of Senology, European Institute of Oncology, Via Ripamonti 435, 20141, Milano, Italy. Tel: +39-02-57489376; Fax: +39-02-57489780; E-mail: oreste.gentilini{at}ieo.it
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Abstract |
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Background: Current guidelines for post-mastectomy radiotherapy (PMRT) derive largely from extrapolating information from multicentre trials. The aim of this study was to describe outcomes of patients who underwent mastectomy without radiotherapy in a single institution.
Patients and methods: 650 patients had total mastectomy and axillary dissection without PMRT between 1997 and 2001. Median follow-up was 65 months.
Results: 5-year cumulative incidence of loco-regional recurrence (LRR) was 6.8% (3.0, 8.1, 9.9% in node negative, 1–3, 
4 positive nodes, respectively). At the multivariate analysis, positive lymph nodes and endocrine non-responsive tumours were found to shorten LRR disease-free survival. In patients with positive hormone receptors, 5-year cumulative incidence of LRR disease-free survival were 2.3%, 7.6% and 7.6% for node negative, 1–3 and 4 positive lymph nodes, respectively. The same figures were 5.9%, 10.3% and 20.0% in patients with endocrine non-responsive tumours.
Conclusions: patients with endocrine-responsive tumours treated by mastectomy and complete (level III) axillary dissection have a low risk of LRR even if four or more positive lymph nodes are involved, thus giving rise to doubts on the use of PMRT in this subset of patients. On the other hand, PMRT might play a role for patients with negative hormone receptors and four or more positive nodes.
Key words: mastectomy, radiotherapy, recurrence, breast cancer, hormone receptor
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The issue of post-mastectomy radiotherapy (PMRT) still appears to be a matter of debate, especially after the publication of an overview on the effects of radiotherapy for breast cancer [1]. In that paper a significant reduction in local recurrence was shown. In addition, for the first time a significant improvement in overall survival was demonstrated after 15 years of follow-up by adding PMRT in node-positive patients. At the European Institute of Oncology, Milan, in patients without skin or thoracic wall involvement, we recommend PMRT in a few very selected cases after total mastectomy and complete axillary dissection, even in patients with four or more positive lymph nodes which usually represents an indication in a number of centres in Europe and the USA [2].
The aim of this study was to retrospectively evaluate and describe patterns of loco-regional recurrence (LRR) in the patients who received mastectomy and axillary dissection without PMRT in a single specialized cancer centre, and also to evaluate predictive factors for relapse.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Between April 1997 and December 2001, 6100 patients were operated on for invasive breast cancer at the European Institute of Oncology, Milan, Italy and were prospectively entered into our data base. We retrieved 650 patients who underwent total mastectomy and complete axillary dissection (CAD), including all three Berg levels, without PMRT. Patients with distant metastases, clinical or pathological T4 or those who received primary medical treatment were excluded from the analysis. Table 1 summarizes the patients' characteristics.
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All patients were prospectively entered into our data base and their cases discussed after surgery at a multidisciplinary meeting attended by breast surgery, medical oncology, radiotherapy and pathology specialists. Regarding adjuvant treatment, 342 patients (52.6%) received both chemotherapy and endocrine therapy, 166 (25.5%) received chemotherapy alone, 126 (19.4%) received hormonal therapy alone and 16 (2.5%) did not receive any adjuvant treatment. None of the patients included in this analysis received PMRT. Four hundred and ninety-one patients (75.5%) also received immediate breast reconstruction. The median age was 48 years (range 23–90). The median follow-up was 65 months (range 14–103). The median number of lymph nodes removed was 23 (range 6–69).
All those patients who had not been seen in the last 6 months were contacted by telephone in order to update the follow-up. No patients were lost at follow-up.
statistical methods
Primary endpoints were loco-regional disease-free survival, disease-free survival and overall survival. Loco-regional disease-free survival was calculated from the date of mastectomy to any LRR, i.e. recurrence to chest wall and/or to lymph nodes, either axillary or supraclavicular, or to last visit date, whichever occurred first. Disease-free survival was calculated from date of mastectomy to any relapse, second primary cancer, contralateral breast cancer recurrence, death or last visit date, whichever occurred first. If patients had simultaneous loco-regional and distant recurrence they were considered as having a distant recurrence in the analysis. Overall survival was defined as the time interval from date of mastectomy to death from any cause or last date of follow-up.
Crude cumulative incidence of local or distant recurrence, whichever occurred first, were computed in a competing risk framework as described by Marubini and Valsecchi [3], and compared across different subgroups by means of the Gray test [4].
The log-rank test was used to assess survival differences between groups in the univariate analysis for the disease-free and overall survival. Multivariate Cox proportional hazards regression models were used to identify the prognostic independent clinico-pathological features associated with survival.
All analyses were performed with SAS software (SAS Institute, Cary, NC, USA) and S-plus software (SPLUS 2000; MathSoft, Inc., Seattle, WA, USA). All tests were two sided.
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results |
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Table 2 describes the events according to tumour size and nodal status. Forty-five patients had a LRR (6.8% 5-year cumulative incidence) with similar incidences with respect to pathological tumour size, whereas, as expected, the risk of LRR increased significantly according to nodal involvement (3.0%, 8.1%, 9.9% 5-year cumulative incidence in node negative, 1–3 and
4 positive nodes, respectively, Gray test P-value 0.006). Two patients had simultaneous loco-regional and distant recurrence, and they were considered as having a distant recurrence.
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Table 3 describes LRR. Seventeen patients (2.6%) had a nodal relapse (5 of these in the axilla and 12 in the supraclavicular region). In those patients with four or more positive nodes the incidence of supraclavicular relapse was 4.5% (7 of 156).
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Furthermore, a second primary tumour was the first event in 14 patients, contralateral breast cancer recurrence in 10 patients and death in 8 patients.
In Table 4 significant predictors of loco-regional disease-free survival, disease-free survival (DFS) and overall survival (OS) are described according to univariate analysis.
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In the multivariate analysis (Table 5) positive lymph nodes (hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.2–6.6 and HR 4.0, 95% CI 1.7–9.8 for 1–3 and
4 positive lymph nodes, respectively) and endocrine non-responsive tumours (HR 1.9, 95% CI 1.0–3.9) were found to worsen LRR disease-free survival.
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Significant predictors of overall survival in the multivariate analysis were: age older than 50 (HR 1.9, 95% CI 1.1–3.1), and age
35 (HR 2.0, 95% CI 1.0–4.6), presence of four or more positive lymph nodes (HR 2.5, 95% CI 1.4–4.5) and absence of estrogen receptor (ER)/progesterone receptor (PgR) (HR 4.4, 95% CI 2.6–7.5). Figures 1(a, b) and 2(a, b) represent cumulative incidence of mortality and LRR in all patients according to nodal status and endocrine responsiveness, respectively.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The indications for PMRT are still controversial, even though well-known guidelines are available [2]. This issue still appears to be very topical, especially after the publication of an overview concerning the effects of radiotherapy [1]. That paper reported for the first time a benefit in overall survival after 15 years of follow-up by adding PMRT in node-positive patients plus an the improvement in local disease-free survival.
These data prompted us to investigate outcome of patients treated by mastectomy and CAD in our specialized cancer institution, and in particular to closely observe the patterns of LRR as our institute operates a strict policy regarding PMRT. In fact, at the European Institute of Oncology, Milan, PMRT is recommended in patients with T4 cancer, and it is usually not performed in patients with four or more positive lymph nodes unless a massive nodal involvement is found. This policy, which is not consistent with the American Society of Clinical Oncology (ASCO) [2] and National Institutes of Health [5] guidelines, is based upon the observation that in the absence of locally advanced disease with skin or thoracic wall involvement, wide surgery with complete axillary dissection (level III) followed by proper adjuvant systemic treatment, represents an adequate loco-regional treatment, providing patients with a good local control. Moreover, it is important to consider the context in which the patient is treated. In fact, our surgical policy comprises a complete removal of axillary lymph nodes up to the apex of the axilla. It therefore seems reasonable to employ different recommendations regarding loco-regional radiotherapy if comparing with institutes in which less extensive axillary surgery (level I and II) is performed [6]. With these data, we would also like to point out that indications, recommendations and guidelines are important in order to achieve the best level of treatment worldwide, but the treatment standards may differ slightly according to the approach of the single centre, once a satisfactory outcome is provided and reported.
The 5-year cumulative incidence of LRR of 6.8% after a median follow-up of 65 months appears to be fairly low and a rate of supraclavicular relapse of 1.8% is acceptable. Even though, as expected, nodal involvement increased the LRR incidence, the subset of patients with four or more positive lymph nodes had an acceptable 4.5% supraclavicular relapse rate, which calls into question the recommendation for PMRT even for this subset of patients.
As expected, in the multivariate analysis the factors which independently affected loco-regional outcome were nodal status and endocrine responsiveness. But the most important finding of this study is that the 5-year cumulative incidence of LRR is quite different according to expression of hormone receptors. In fact, local control and overall survival of patients with endocrine-responsive tumours were satisfactory even in node-positive patients (7.6% LRR rate in both 1–3 and 4 positive nodes). On the other hand, the cumulative incidence of LRR was 5.9%, 10.3% and 20.0% for node-negative, 1–3 and 4 positive lymph nodes, respectively, in patients with endocrine non-responsive tumours. Therefore, when ER and PgR are positive the cumulative incidence of LRR is also acceptably low in the so-called ‘high risk’ group of patients with four or more positive nodes, whereas when hormone receptors are not expressed, the 5-year cumulative incidence of LRR of 20% in patients with four or more positive nodes requires outcome improvement. These results appear to be reasonable in the sense that the biology of breast cancer influences the prognosis of the disease [7–9]. Moreover, we can speculate that effective medications are available for the long-term treatment of hormone receptor-positive breast cancer, whereas six courses of chemotherapy are usually administered to patients with ER- and PgR-negative tumours, without any other long-term treatment in case HER2/neu is not over-expressed.
We believe that the philosophy of adjuvant treatment of breast cancer should be modified towards being more tailored to the features of the disease rather than towards the risk of recurrence. The fact that a high risk of recurrence is theoretically conceivable on the basis of nodal status only does not mean by itself that any further treatment is going to improve outcome. The data from our study support this concept which is aimed not only at improving prognosis for those patients who are likely to benefit from a certain type of therapy, but also aims to spare patients from treatments which have an unfavourable side-effect/benefit ratio. From this standpoint, patients with endocrine-responsive tumours treated by mastectomy and complete axillary dissection have a low risk of LRR even with four or more positive lymph nodes, and therefore the benefit of adding PMRT appears to be questionable in this subset of patients. PMRT might play a role in patients with negative hormone receptors and four or more positive nodes.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The authors greatly appreciated the contribution of Mr William Russell-Edu for language revision.
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Footnotes |
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All listed authors directly contributed to the manuscript: O.G. conception of the study, interpretation of data and drafting the manuscript; E.B., N.R., S.G. analysis of data; M.I., G.G., A.L., P.V., V.G. critical revision of the manuscript; L.S., N.P., R.C.S. acquisition of data; A.G. and U.V. interpretation of data, drafting the manuscript and final approval. 
Received for publication March 13, 2007. Revision received April 4, 2007. Accepted for publication April 5, 2007.
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References |
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5. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference statement: adjuvant therapy for breast cancer November 1–3, 2000. J Natl Cancer Inst (2001) 93:979–989.
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