The Benefit of Surgery in Stage IV of Breast Cancer
The Benefit of Surgery in Stage IV of Breast Cancer
Treatment of Metastatic Breast Cancer is not usually considered curative. Recent
 retrospective studies have demonstrated that resection of the breast tumor in patients with
 primary metastatic breast cancer is associated with a significant improvement of the
 prognosis. In all these aforementioned studies, the decision to perform surgery could have
 been influenced by favorable prognostic factors, such as younger age, the presence of only
 one metastatic site, or good response to systemic therapy. To rule out the impact of
 potential confounders, most studies adjusted for age, tumor size, number and sites of
 metastases and hormone receptor status. In addition, some studies also adjusted for
 comorbidity or surgical margins. For example, in the study of Bafford et al., the benefit of
 surgery seemed confined to patients operated upon before diagnosis of metastatic disease and
 there was no survival advantage in patients who received an operation of the breast tumor
 after the diagnosis of the metastatic disease had taken place. This phenomenon was referred
 to as the stage migration bias. In a study by Leung et al., the benefit from surgery
 disappeared in the multivariate analysis when taking into account the use of chemotherapy.
 Finally, in a study by Cady et al. coding errors in the retrospectively collected dataset
 were found to explain part of the survival advantage. 4Therefore, this randomized controlled
 trial (RCT) has been initiated.

 In the literature, several retrospective studies noted that 35-60% of patients with
 metastatic cancer at the time of diagnosis received local treatment of primary lesions, which
 resulted in a positive impact on survival. However, an analysis of 16,023 patients presenting
 with stage IV disease and an intact primary tumor compared outcomes between patients having
 surgery of the primary tumor to negative margins or no surgery. In a multivariate analysis
 adjusting for known prognostic factors, surgery reduced the HR for death to 0.61 (95% CI =
 0.58 to 0.65). Multiple other retrospective studies from single institutions, registries, and
 population-based cohorts have confirmed this initial observation, but it is uncertain whether
 these studies reflect a real benefit for surgery or consistent selection bias. Three
 prospective randomized trials are examining the role of surgery in patients presenting with
 stage IV disease and an intact primary tumor. While awaiting the results of these trials, it
 is not known precisely how or when to integrate such surgical management into a standard
 medical therapy for metastatic breast cancer or which patients, in particular, are most
 likely to benefit from such treatment. 1 The aim of this study is to investigate the effect
 of surgery of the primary tumor in breast cancer patients with distant metastatic disease at
 initial diagnosis. According to the controversies in previous studies design of a study with
 the least confounding factor to decrease the bias seems to be necessary.
After the diagnosis of primary distant metastatic breast cancer, patients will be randomly
 allocated into two groups: A. systemic therapy followed by surgery if the disease is not
 progressive; B. Systemic therapy Patient selection criteria

 The eligibility criteria for the study are:

 - primary distant metastatic breast cancer (M1); - an anticipated survival of at least 6
 months; - a histologically proven diagnosis of the breast tumor; - a known hormonal and
 HER2Neu status; - TNM classification: T1-T3, resectable T4 status, and N0-N3; - performance
 status and comorbidity should allow surgery and/or systemic therapy; - age ≥ 18 years;-
 written informed consent.

 Exclusion criteria are:

 - primary invasive breast cancer in the medical history; - another malignancy within the last
 10 years, besides basal cell carcinoma of the skin or early-stage cervical cancer; - surgical
 treatment and/or radiotherapy of the breast tumor before randomization; - irresectable T4
 breast tumor; - synchronous bilateral breast cancer.

 Randomization Centralized randomization will take place immediately after the diagnosis of
 primary distant metastatic breast cancer, using computer-generated randomization. dominant
 location of distant metastases (bone, soft tissue (lymph nodes and subcutaneous metastases)
 and visceral metastases), hormonal receptor status (ER and/ or PR positive or both negative)
 and HER2Neu status (overexpression yes or no) will be recorded.

 Settings and location The study is a randomized controlled trial, which will be conducted at
 Tehran University of medical sciences, imam Khomeini hospital Treatment options During the
 study patients can be treated with surgery of the primary tumor (depending on randomization),
 systemic therapy The different treatment modalities are described below. Patients who are
 randomized to upfront surgery of the breast tumor will receive a lumpectomy or mastectomy
 depending on patient and tumor characteristics. Both types of surgery may be conducted as
 long as the intention is complete resection of the primary tumor, which is defined as having
 succeeded in obtaining free resection margins for the invasive component. The choice to
 perform an axillary lymph node dissection is left to the discretion of the treating physician
 but is highly recommended if palpable and/or tumor positive lymph nodes in the axillary
 region are present. If patients are randomized for systemic therapy, they may still be
 candidates for surgery of the primary tumor. In the case of local progression, breast surgery
 is allowed at any time to gain local control. Surgery for this group is primarily indicated
 when the treating physician beliefs the tumor may cause wound problems in near future,
 despite the use of systemic therapy. Patients will be treated with systemic therapy according
 to the guidelines. The choice of initial chemotherapy, immunotherapy, and endocrine therapy
 depends-among others-on ER and PR and HER2Neu status, dominant site of distant metastases,
 age, performance status, and comorbidity; but may also depend on the chance to reach a
 complete remission for example in minimal metastatic disease. In patients with a hormone
 receptor-positive tumor, hormonal treatment is indicated. In the case of rapid progression,
 chemotherapy is the treatment of choice. In HER2Neu positive disease and the use of an
 aromatase inhibitor, it is possible to add HER2Neu targeted therapy. Chemotherapy is offered
 to patients with hormone receptor-negative status, with extensive and fast-growing visceral
 metastases. For this study, we advise using at least an anthracycline, a taxane, and
 cyclophosphamide for the first 2-3 lines of treatment, if necessary in combination with
 targeted therapy, such as HER2- Neu targeted therapy, according to local practice.

 Primary and secondary outcome measures The primary endpoint is the two-year survival. This is
 defined as the percentage of patients who survive two years after randomization. Secondary
 endpoints are quality of life, overall survival, number of unplanned local therapies, i.e.
 surgery or radiotherapy, number of axillary lymph node dissections or axillary radiotherapy,
 determination of pathological resection margin (margin status) in patients treated by surgery
 of the primary tumor.

 Statistics Sample size calculation We are planning a randomized controlled trial with an
 equal number of patients in both treatment arms, an accrual interval of 36 months. Sample
 size calculation

 Step 1: Calculation of the number of events with the following formula:

 α=0.05 zα/2= 1.96 β=0.20 Zβ=0.84 π1=π2= 1/2: Equal allocation HR =0.50 Event =66

 Step2: Calculation of the number of Patients with the following formula:

 In this step, we assume the 40% of patients will die during the 2-years follow-up of the
 study. So the total number of desired patients will be 212. Therefore we need 106 patients in
 each group. Considering a 10% loss of patients, we should enter 118 patients in each group.

 Following calculations were conducted:

 Follow-up period= 2 years Suppose Incidence Rate (IR) = 25 events/person-2 years λt=0.5 at t=
 2-year S(t)= exp{-λt}= exp{0.5}=0.60 1-0.60= 0.40 It means 40% of patients will die during 2
 years of follow-up.

 S1(2)= exp{-0.5}=0.60 S2(2)=exp (-0.5* HR}=0.78 Pr {event} = 1- {(0.60+0.78)/2}=0.31 N=
 66/0.31=212 Total number n=106 each group

 Number after considering 10% loss =118 /group

 Data analysis Investigators will enter the information required by the protocol into the Case
 Report Forms (CRFs). The data from all investigators will be pooled and summarized with
 respect to demographic and baseline characteristics and efficacy and safety observations.
 Data will be presented for the complete intent-to-treat population. The primary endpoint will
 be analyzed in a Cox regression model, with the minimization factors as covariables. Interim
 analysis
Inclusion Criteria:

 Primary confirmed distant metastatic breast cancer (M1); A histologically proven diagnosis
 of the breast tumor; A known hormonal and HER2Neu status; Having TNM classification: T1-T3,
 resectable T4 status, and N0-N3; - performance status and comorbidity should allow surgery
 and/or systemic therapy; Accepting the surgery by written informed consent.

 Exclusion criteria are:

 No confirmed primary invasive breast cancer in the medical history Having another
 malignancy within the last 10 years, besides basal cell carcinoma of the skin or
 early-stage cervical cancer Having the history of surgical treatment and/or radiotherapy of
 the breast tumor before randomization Having irresectable T4 breast tumor Having
 synchronous bilateral breast cancer.

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