Breast conserving surgery after neoadjuvant therapy for large primary breast cancer

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EJSO 34 (2008) 863e867

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Breast conserving surgery after neoadjuvant therapy for large primary breast cancer D.G. Tiezzi*, J.M. Andrade, H.R.C. Marana, F.E. Zola, F.M. Peria Department of Gynecology and Obstetrics, Breast Disease Division, Hospital das Clı´nicas of Ribeir~ao Preto School of Medicine, University of S~ao Paulo, 3900 Bandeirantes Ave, Monte Alegre, 8 floor Ribeir~ao Preto, S~ao Paulo 14048-900, Brazil Accepted 16 January 2008 Available online 4 March 2008

Abstract Aim: The aim of this study was to evaluate the safety of breast conserving surgery in patients with breast tumours satisfactorily downstaged after neoadjuvant therapy. Methods: A retrospective cohort study was undertaken to analyze the loco-regional recurrence (LRR) after breast conserving surgery. We enrolled 88 patients with breast cancer subjected to neoadjuvant therapy (NAT group) who achieved an objective response due to neoadjuvant treatment and compared them with 191 patients with early breast cancer (EBC group) who were submitted to primary conserving surgery. Lumpectomy or quadrantectomy with axillary lymph node dissection was performed in all patients who received adjuvant radiotherapy. Systemic adjuvant therapy was offered to all patients. The mean periods of observation were 61.3 months in the NAT group and 67.5 months in the EBC group. Results: The mean age was 53 years in the NAT group and 56 years in the EBC group ( p ¼ 0.04). There was no histological type and histological grade difference between groups. In the NAT group, the mean diameter of residual tumour was lower and the mean volume of breast tissue resection was higher than in the EBC group ( p ¼ 0.01 and p ¼ 0.002, respectively). The ipsilateral recurrence rate was 7.9% in the NAT group and 7.8% in the EBC group ( p ¼ 0.9). The most important predictive factor of recurrence in the NAT group was the age of patient. Conclusion: Breast conserving therapy is a safe procedure in satisfactorily downstaged breast cancer after neoadjuvant therapy. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Breast cancer; Neoadjuvant therapy; Surgery; Breast conserving therapy; Loco-regional recurrence

Introduction Patients with large tumours are not suitable to breast conserving surgery (BCS) for obvious reasons. Instead, neoadjuvant or induction chemotherapy (NACT) is used to reduce the primary tumour by transforming locally advanced lesions into early breast tumours. Randomized trials have reported satisfactory downstaging rates between 49% and 94% with induction chemotherapy for operable breast cancer.1e7 However, the safety of performing breast conserving treatment in such patients has not yet been defined. The partial breast resection after neoadjuvant chemotherapy remains controversial. This fact is based on the

* Corresponding author. Tel.: þ55 16 36022583; fax: þ55 16 36330946. E-mail address: [email protected] (D.G. Tiezzi). 0748-7983/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2008.01.015

observation that tumour shrinkage patterns are not concentrical.6,8 The microscopic residual tumour surrounding the post-chemotherapy lump is the major objection to breast conserving therapy after NACT. This observation led Veronesi et al. to propose quadrantectomy to all patients with large tumours submitted to induction chemotherapy, regardless of clinical response.8 On the other hand, three major points support the hypothesis that BCS is a safe option for downstaged breast cancer patients. First, about 20% of patients achieve complete pathological response.1e4,6,7 Second, there is significant evidence that radiotherapy is able to sterilize the microscopic residual tumour. Finally, recent studies concerning the efficacy of imaging diagnostics in predicting residual tumour after neoadjuvant chemotherapy have shown that concentric tumour shrinkage is the most common pattern of tumour regression in patients with partial response.9

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Based on the current acceptance of BCS in patients with early breast cancer, we propose to compare, in a retrospective cohort study, the loco-regional recurrence rate after BCS between patients with original early breast cancer and patients with large tumours who achieved satisfactory downstaging after NACT. Patients and methods Study design All patients submitted to BCS between January 1990 and December 2003 were included in the study. The early stage breast cancer (EBC group) comprised 191 patients clinically staged as I, IIa, and IIb (T2, N1, M0) with T  3 cm. Eighty-eight patients were subjected to neoadjuvant therapy (NAT group). They were clinically staged as IIa (T2N0M0) with T > 3 cm, IIb (excluding T2N1M0 with T  3 cm), or III, and they were not suitable to primary BCS. Inflammatory carcinoma was an exclusion criterion. The study was approved by the local ethic committee. Neoadjuvant systemic therapy Exclusive chemotherapy was delivered to 73 patients with either a combination of docetaxel (75 mg/m2) plus epirubicin (60 mg/m2) [39 patients]; FEC60 (fluoruracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2) [25 patients]; paclitaxel (135 mg/m2) and epirubicin (60 mg/m2) [four patients]; epirubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) [one patient]; sequential FEC60 and docetaxel/epirubicin (two patients) or a combination of taxane plus trastuzumab (two patients). All squemes were i.v. infusion D1 each 21/21 days. Thirteen patients were submitted to neoadjuvant hormone therapy: tamoxifen 20 mg (11 patients) or letrozol 2.5 mg (two patients) both P.O. daily. The remaining two patients were treated with chemo and hormone therapy combination (FEC60 or docetaxel/epirubicin plus tamoxifen). Neoadjuvant therapy was administered until allowing BCS. The patients were examined after each cycle and the response was recorded by clinical measurement of the two largest tumour diameters. NAT patients were selected for surgery if satisfactory tumour downstaging was achieved (partial or complete clinical response10 with no residual tumour larger than 3 cm in the greatest diameter). The median number of neoadjuvant chemotherapy delivered was three cycles (2e5), and the median time of neoadjuvant endocrine therapy was three months (3e5). Surgical procedure For both groups, the eligibility criteria for BCS were defined after clinical and radiological examination. All patients subjected to BCS achieved negative margins in the intraoperative standard assessment. This procedure

may require lumpectomy or quadrantectomy followed by axillary lymph node dissection levels I, II, and III. Patients with close or involved margins in the definitive pathologic assessment were candidates to re-operation. However, in 42 patients, the re-operation was not performed. Among them, margins were close or involved by in situ carcinoma in 25 patients and focally involved by invasive carcinoma in 17. The re-excision was not performed either by refusal (six patients) or technical impossibility (posterior margin involving the major pectoral muscle fascia). Adjuvant systemic therapy Adjuvant chemotherapy was offered to 76 patients in the NAT group and to 116 patients in the EBC group. Eligibility criterion to adjuvant chemotherapy in the EBC group was tumours greater than 1 cm (pT1c) or with axillary lymph node metastasis if the Karnofski performance status was greater than 70% and the patient age 75 or younger. The chemotherapy followed the CMF scheme (cyclophosphamide 600 mg/ m2, methotrexate 60 mg/m2 and 5-fluoruracil 600 mg/m2 i.v. infusion D1 each 21/21 days) for patients with three or fewer axillary lymph node (ALN) metastases, or the FEC60 scheme for patients with more than three ALN metastases. In the NAT group, a total of nine cycles of chemotherapy was given. The total treatment includes the neoadjuvant plus adjuvant settings. In the EBC group, patients received six cycles of adjuvant chemotherapy. Adjuvant hormone therapy with tamoxifen was offered to all patients with either known positive hormonal receptor, menopausal status defined by 1 year of period cessation, or prior bilateral oophorectomy in patients with unknown hormonal receptor status. Adjuvant radiation therapy Radiotherapy was administered with a standard technique using medial and lateral tangential fields to deliver a total dose of 50 Gy on the whole remaining breast tissue. Supraclavicular fossae standard radiation therapy was applied to all patients with four or more ALN metastases. A total dose of 10 Gy of radiotherapy was delivered additionally as a boost to the tumour bed to all patients with close or involved margins. Surgical specimen records The following characteristics were recorded from the excised specimens: dimensions of the excised breast tissue, macroscopic dimensions of the tumour, histological tumour type, presence of an extensive intraductal component (EIC), axillary node involvement, and the status of the resection margins on macroscopic and histological examination. Negative margins were considered if the smallest margin was greater than 1 mm.11 The total volume of excised breast tissue was calculated for the 268 patients for whom three dimensions of each specimen were recorded.

D.G. Tiezzi et al. / EJSO 34 (2008) 863e867

The formula for ellipsoid body volume calculus was used [(4/3)  pi  radius1  radius2  radius3] to estimate the total volume of breast tissue resection.

Table 1 Characteristics of 88 patients treated with neoadjuvant therapy (NAT group) and 191 patients with early stage breast cancer (EBC group) subjected to breast conserving therapy NAT (n ¼ 88)

EBC (n ¼ 191)

p

Age (mean) Clinical stage 0 I IIa IIb

53 After CT 21 19 43 5

56

0.04

8 80 95 8

<0.001

Local treatment QUART TART

23 65

44 147

NS

Histological type Ductal Others

76 12

172 19

NS

Histological grade I II III NA Specimen volume (mean) Tumour diameter (mean)

19 51 9 9 108 1.6

61 103 16 11 78 1.9

NS 0.002 0.01

Axillary status 3 >3

72 16

175 16

0.02

Margin status Close/involved Negative

17 71

25 166

NS

Hormonal receptor Negative Positive Unknown

17 40 31

20 80 91

Follow-up For the first 2 years after treatment, a medical visit was scheduled once every three months. From the third to fifth years, patients returned every six months, and annually thereafter. Screening mammography was taken six months after definitive surgery and annually thereafter. Local recurrence diagnoses were confirmed through core or open biopsy and histological evaluation. All patients with known local recurrence were subjected to salvage mastectomy. The mean follow-up was 61 months and 67 months in the NAT and EBC groups, respectively. Endpoints The primary endpoint was the loco-regional recurrence (LRR) rate comparing early breast cancer patients subjected to primary BCS, and breast cancer patients subjected to primary systemic therapy with satisfactory downstaging followed by BCS. The definition of ipsilateral recurrence (ILR) was the histological confirmation of the disease with similar histological pattern in the same breast quadrant of the primary tumour. Late ipsilateral recurrence (more than 5 years after primary surgery) and contra-lateral recurrence were considered as new primary tumours.12e14 Additionally, we tried to identify predictive factors for ipsilateral recurrence. We tested the risk of LRR according to clinical (age, clinical stage) and pathological characteristics (tumour diameter, specimen volume).

865

NS

Loco-regional recurrence Statistical analyses Comparisons of characteristics of patients between NAT and EBC groups were performed by a Student t test (age), Chi-square test (clinical stage and histological grade), Fisher’s exact test (type of surgery, histological type, axillary lymph node metastasis and hormone receptor expression), and Wilcoxon test (volume of surgical specimen and diameter of tumour). The local recurrence rate was analyzed by Fisher’s exact test and by a KaplaneMeier curve. The LogRank test was used to analyze the disease-free and overall survival curves. The predictive factors of ipsilateral recurrence were analyzed by logistic fit and Fisher’s exact tests. A proportional hazard fit was used for multivariate analysis of ipsilateral breast recurrence.

The overall loco-regional recurrence rate, including ipsilateral and contra-lateral breast recurrence, was 12% in the EBC group and 11% in the NAT group ( p ¼ 1.0). We observed a new primary breast tumour in eight patients in the EBC group and in three patients in the NAT group. The ipsilateral recurrence rate (ILRR) was 7.8% in the EBC group and 7.9% in the NAT group ( p ¼ 0.9). Disease-free and overall survival

Results

During the follow-up, in the EBC group, 16 patients developed distant metastasis, and 11 patients died due to disease progression. Among patients in the NAT group, 19 patients developed metastatic disease, and 14 patients died due to disease progression. There was a significant difference in DFS ( p ¼ 0.001) and in OS ( p ¼ 0.005) favouring the EBC group.

Characteristics of patients

Predictive factors of ipsilateral recurrence

Table 1 outlines the characteristics of patients in both the NAT and EBC groups.

We analyzed clinical features (age, number of chemotherapy cycles, use of taxanes in neoadjuvant setting,

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clinical tumour diameter, axillary status, the use of chemotherapy and hormone therapy in adjuvant setting and the type of surgery performed) and pathological features (pathological tumour diameter, histological type and grade, presence of EIC and multicentricity, presence of axillary lymph node metastasis, margins status and hormonal receptor expression) as predictive factors of ipsilateral breast recurrence in the NAT and EBC groups. Only the volume of surgical specimen ( p ¼ 0.02) and the age of patients ( p ¼ 0.001) were predictive factors for ipsilateral recurrence in univariate analysis in the NAT group. Thirteen elderly patients (mean age of 72 years) were subjected to primary endocrine therapy, and none presented loco-regional recurrence. Among 70 patients treated with primary chemotherapy (mean age of 49 years), the ipsilateral recurrence rate was 9% and the ipsilateral recurrence rate in 11 patients under 41 years was 36%. In the subset of patients with early breast cancer, similar results were observed: no ipsilateral recurrence in patients over 70 years (mean age of 75 years) and 9% in patients fewer than 71 years (mean age of 52). The ipsilateral recurrence rate in 22 patients under 41 years in the EBC group was 18%. A proportional hazard fit for multivariate analysis of significant variables in a univariate test in the NAT group showed that only the age significantly correlated with the risk of ipsilateral recurrence (risk ratio ¼ 0.8; 95% CI of 0.8e0.96). Discussion Neoadjuvant therapy has become an alternative treatment to increase the BCS rate for breast cancer patients enabling partial breast resection in 50e75% for patients with primary tumours suited to mastectomy.15e17 Current studies have demonstrated that the long-term outcome is highly correlated to the response to neoadjuvant chemotherapy, and a higher response results in improved survival that is proportional to the pathological complete response rate.4,21 Afterward, the emerging trend in neoadjuvant settings is to achieve the highest response before performing the local surgical treatment.18 Consequently, an increasing number of large primary tumour patients will be eligible for BCS. The safety of BCS in patients with large tumours downstaged by neoadjuvant therapy remains controversial. Indeed, several groups have reported unacceptably high recurrence rates for patients who underwent BCT after NAT.19e22 The results from the NSABP B-18 trial reported an ipsilateral breast tumour recurrence rate of 16% at 9 years among patients considered to mastectomy at diagnosis.10 However, acceptable rate of ipsilateral recurrences in a 5-year follow-up (6%) was reported in one of the largest single-institution studies19 and from other authors.23e25 We compared the local recurrence rates after BCS between a group of patients with original early breast

cancer and a group with large primary tumours that were satisfactorily downstaged after NAT. We observed a similar ipsilateral recurrence rate in both groups. The discrepancy in outcome observed among different studies can be explained basically by patient selection criteria. Conversely, as in the case with the NSABP B-18 protocol that included patients who were or were not eligible to BCS, all the patients we included in the NAT group were considered for primary mastectomy or had inoperable lesions, and all patients had a clinical response sufficient to allow breast segmental resection. In a subset analysis of patients who were primarily considered for mastectomy, the ILRR is higher in the NASBP trial than we observed among our patients. However, the published NASBP report does not allow us to analyze the clinical and pathological stage after chemotherapy. In our study, clinical and pathological T stages after neoadjuvant treatment in NAT were quite similar to the EBC group. Patients’ characteristics, including age10 and pretreatment tumour stage,19 have been reported as predictive factors of local recurrence. Our findings indicate that age can affect the rate of ILR for patients treated with BCS after neoadjuvant chemotherapy. ILR was not observed in patients older than 70 years. Conversely, the 5-year ILR rates in patients under 41 years were 36% in the NAT group. The high rate of local recurrence in this subset of patients is a limiting factor for BCS and the desire for breast conservation should be taken into account in the treatment options. The role of residual tumour in ILRR was well demonstrated in a previous report.19 The authors demonstrated that tumours with a multifocal residual pattern after primary chemotherapy had a higher risk of developing local recurrence. It is assumed that the risk of residual microscopic disease after surgical excision is higher in this group of patients when compared with patients whose tumour shrinkage occurred concentrically. Our study did not evaluate the shrinkage pattern. However, we were the first investigators to evaluate the volume of breast resection and its role in predicting local recurrence. Following neoadjuvant treatment, we observed that there were more patients with non-palpable lesions, and the mean of pathological diameter of tumours was lower in the NAT group compared with the EBC group. Patients treated with BCS, after primary systemic therapy, were subjected to larger breast tissue resection than patients with original early stage breast cancer. Thus, a larger amount of breast tissue surrounding the main lump was excised in the NAT patients. This observation emphasized the role of surgical resection as part of local control in breast cancer.26 Our data demonstrated that BCS in satisfactorily downstaged breast cancer is as safe as the same procedure in original early stage breast cancer. The main limiting factor BCS after neoadjuvant therapy is the young age.

D.G. Tiezzi et al. / EJSO 34 (2008) 863e867

Conflict of interest All the authors declare to have no conflict of interest.

12.

Acknowledgments

13.

This research was supported by a grant from Fundac¸~ao de Apoio ao Ensino, Pesquisa e Assisteˆncia (FAEPA) of the HCFMRP-USP, Brazil.

14.

15.

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