Primary Surgery Compared to Post Chemotherapy Surgery for Patients with Locally Advanced Breast Cancer

Purpose: To compare primary surgery and surgery after 
neoadjuvant chemotherapy (NCT) in locally advanced breast cancer (LABC) 
patients. Methods: Between January 2011 & December 2015, 112 
patients with LABC were treated at KAAH & OC-Jeddah-KSA, Of whom 42 were treated by 
NCT followed by surgery either mastectomy or conservative surgery, then 
adjuvant chemotherapy and radiotherapy. The rest patients (70) were treated by 
primary surgery (mastectomy or conservative resection) and followed by adjuvant chemotherapy and radiotherapy. 
All patients received adjuvant antiestrogen. Patients were followed for a 
median duration of 33 months. Disease-free survival (DFS) and overall survival 
(OAS) were studied for all patients, compared between both groups and related 
to the extent of surgery and menopausal status. Results: median age was 
46.5 years for all patients; 48 years, and 46 years for 
NCT and primary surgery groups respectively. Median DFS was 15 months for all 
patients, 16 & 15 months for NCT and primary surgery groups. Median OAS was 
24 months for all patients, 22 & 24 months for NCT and primary surgery 
groups. Difference in DFS & OAS were highly significant in favour of 
postmenopausal patients (p = 0.05 for DFS & p = 0.03 for OAS) while in 
primary surgery group the differences between pre and postmenopausal patients 
in DFS & OAS were statistically insignificant (p = 0.4). NCT followed by 
surgery group patients showed significant improvement in DFS & OAS in 
patients performed conservative surgery while in primary surgery group the 
difference was insignificant. Freedom of disease was seen in 28.6% in the NCT 
group and 37.1% for the primary surgery group. Conclusion: Surgery 
post-neoadjuvant chemotherapy neither prolongs DFS nor OAS in comparison with 
primary surgery followed by adjuvant chemotherapy. Postmenopausal patients felt much better than premenopausal patients regarding 
DFS & OAS.


Introduction
Locally advanced breast carcinoma (LABC) comprises a heterogeneous group of tumors ranging from relatively large primary tumors (stage T4) to small breast tumors presenting with extensive nodal metastases (involvement of ipsilateral, infraclavicular, supraclavicular, or internal mammary nodes). It remains a clinical challenge as the majority of patients with this diagnosis develop distant metastases despite appropriate therapy [1] [2]; inflammatory carcinomas also included in locally advanced breast carcinoma [3]. It is defined by 1992 American Joint Committee (AJC) staging criteria for stage IIIa and IIIb disease [4]. Despite the awareness of physician and public of the importance of screening and early detection, 10% -20% of women with breast cancer have the locally advanced disease at diagnosis in industrialized countries (14% in the United States) while in developing countries it might constitute up to 50% of incident cases [5]. In populations that receive regular screening mammography, the percentage of patients with the locally advanced disease is less than 5% [6].
The treatment for patients with locally advanced breast cancer is typically a combination of systemic chemotherapy, surgery, and radiotherapy. There is a consensus that all patients with the technically resectable disease should have radical mastectomy [4]. Earlier results of radical mastectomy alone were associated with a 53% local failure rate and a zero% 5-year disease-free survival [7]. Similarly radiation therapy alone for these patients resulted in poor 3-year survival (10% -25%) with significant risk for disease recurrence and death, as well as the complications of soft tissue, ribs, heart and lung injury, also brachial plexopathy, lymphedema, chest wall fibrosis, skin ulceration, and skin necrosis [7]. Although the combination of surgery and radiotherapy decreased incidence of local failure, a high frequency of distant metastasis was seen after either treatment approaches. The introduction of multimodality treatment with the addition of chemotherapy has resulted in improvement of disease-free survival particularly in stage IIIA [4] [7].
Neoadjuvant chemotherapy (NCT) was developed in 1970 and is used before local treatment in LABC to downstage the primary tumor to make subsequent surgery easier, hoping to eliminate distant occult metastasis to prolong survival [8]. The natural history of this disease has been changed dramatically by the introduction of these combined modality therapies with the 5-year survival rate of 35% -60% commonly are reported [5]. Despite the theoretical and experimental data indicating the survival superiority of neoadjuvant chemotherapy over postoperative adjuvant chemotherapy, the role of neoadjuvant in staging remains unclear [8] [9], and there are few studies that compare this approach to

Results
The median age for the whole group was 46.5 years, and the mean age was 46.19 ± 14.69 years (range 23 -75), and the peak age was in the third and fourth decade, which represents 50% of all patients (Table 1). No difference was noticed in the median age between neoadjuvant chemotherapy group (NCT) and surgery or adjuvant group (surgery) 48 and 46 years respectively ( Table 2) Premenopausal patients constitute 62.5% of whole patients while 37.5% were postmenopausal. In both studied groups (NCT) and (surgery) 57% and 56% were premenopausal while 43% and 35% were postmenopausal respectively (  (Table 3).
These differences were also noted in NCT followed by surgery group where DFS was 10.5 months for premenopause and 29 months for postmenopause with (p = 0.05) and OAS was 15.5 months and 35 months for pre and post menopause respectively (p = 0.03). In the primary surgery group this difference in DFS and OAS for pre and post menopause was statistically insignificant (p = 0.4) ( Table   4).
Although the noticed improvement of DFS in NCT followed by surgery group

Discussion
Locally advanced breast carcinoma is associated with a poor prognosis; with single treatment modality, i.e., surgery, and/or radiotherapy, results have been consistently dismal [11]. The appropriate management of locally advanced breast cancer is controversial, the trends towards a more effective means of improving response rates and survival have shifted to earlier aggressive treatment, and the strength in the management of LABC lies in the team approach to multimodality care [12]. The sequence of treatment in those patients still has to be optimized since despite the theoretical and experimental data indicating the survival superiority of neoadjuvant followed by surgery over downstaging of the primary tumor is confirmed [9]. In the present study which aimed at comparison of patients treated with neoadjuvant chemotherapy followed by surgery and those operated by a primary operation followed by adjuvant chemotherapy, analysis of data revealed that the median age was 46.5 years and the mean was 47.19 ± 14.69 years. This median age was also reported from a similar study performed in KFSH-Riyadh study [13]. This mean age is not different from the overall age incidence for breast cancer in Saudi Arabia, which reported mean age at diagnosis to be 48.3 years, Cancer Incidence Saudi Arabia [14]. Premenopausal patients comprise 62.5% of all patients and 37.5% postmenopausal, and this incidence was similar to that reported by KFSH-Riyadh [15].
Analysis of survival data revealed that the median DFS in our patients was 16 months, a similar figure (17 months) was reported in a similar study [15] [16].
No difference in DFS and OAS was noticed in patients treated by NCT followed by surgery or by primary surgery, and this finding has been documented by [17] who compared preoperative with postoperative therapy in operable breast  [20]. For this reason, recent trials and utilizing aggressive chemotherapy with newer agents like Texas [21] [22] or by increasing dose intensity in conjunction with growth factors to increase the response of the tumors to primary chemotherapy which may improve the survival and this is reported in southwest oncology group phase II trials [23].
On the other hand in NCT followed by surgery group, there was the discrepancy in the results since there was the significant difference in survival parameters (DFS and OAS) favoring patients who performed conservative surgery. However, this finding could be explained by the fact that patients who performed conservative surgery were those who showed excellent response to primary chemotherapy and they achieved better results than those who showed minimal response to chemotherapy and consequently performed modified radical mastectomy did. These results were also reported by Schwartz

Conclusion
The results of this study showed that primary surgery followed by postoperative therapy is comparable to neoadjuvant treatment followed by surgery in LABC regarding disease-free survival, overall survival, distant failure, and disease control. However, local recurrence was higher in NCT followed by surgery group because of the favorability of conservative resection in both patients and surgeons side once they got tumor shrinkage, but we have to give attention to what was reported about this situation by [26] who found that chemotherapy is useful in reducing tumor size to allow surgical resection but does not sterilize the breast of cancer, and they caution against the use of any surgery less than total mastectomy in partially responsive tumor if optimal local control is to be achieved in locally advanced breast cancer. Secondly, the post menopause (older age) patients felt much better than the younger generation regarding survival parameters particularly with NCT followed by surgery group. So, we recommend that younger patients who deserve neoadjuvant chemotherapy have to be treated aggressively by surgery not less than mastectomy. The other alternative is the use of a newer chemotherapeutic agent or increasing dose intensity of chemotherapy to obtain a higher clinical and pathological remission so that conservative surgery could be performed with optimal local control and reducing distant failure [29] [30]. Neoadjuvant chemotherapy will also provide a useful biological model to assess the effects of systemic treatment on the primary tumor and regional metastases, in addition to hoping to reduce distant failure.