Capecitabine in Combination With Aromatase Inhibitor Versus Aromatase Inhibitors, in Hormonal Receptor Positive Recurrent or Metastatic Breast Cancer Patients, Randomized Controlled Study
Capecitabine in Combination With Aromatase Inhibitor Versus Aromatase Inhibitors, in Hormonal Receptor Positive Recurrent or Metastatic Breast Cancer Patients, Randomized Controlled Study
Women with recurrent or metastatic breast cancer who are hormone receptor positive are
 candidates for first line hormonal therapy including aromatase inhibitors. In the past few
 years new combination therapies became available as fulvastrant or palbociclib with
 letrezole; increasing the progression free survival (PFS). A retrospective study showed that
 combination of capecitabine with aromatase inhibitors increase PFS as 1st and 2nd line line
 treatment another prospective study showed the same results. The aim of our study is confirm
 such data by a randomized controlled trial.
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death
 among women worldwide, accounting for 25% of total cancer cases (Globocan, 2012) It ranks as
 the most prevalent cancer among women in the Middle East and Northern Africa (Ferlay et al.,
 2015). In Egypt, breast cancer is the most common type of cancer among females (Ibrahim et
 al., 2014).

 Survival of breast cancer patients depends on the disease stage. Most of the patients with
 localized disease experience long-term disease-free survival. Meanwhile, those who develop
 metastasis have a 5-year relative survival of only 24% (Siegel et al, 2015). Hormonal
 receptor positive (HR +ve) represent the most common subset (almost 70%) in both early and
 advanced disease (Clarke et al., 2012).

 It is crucial to determine the menopausal status before initiation of treatment. For HR +ve /
 Her 2-negative metastatic breast cancer patients who premenopausal; If the patient had
 Disease free survival (DFS) of 12 months or more, or if she was diagnosed with metastasis de
 novo, the recommended first line is either ovarian ablation plus tamoxifen or aromatase
 inhibitor (Cardoso et al., 2017). For postmenopausal patients aromatase inhibitors are
 recommended with median progression-free survival (PFS) between 8 and 10 months (Bonneterre
 et al., 2000) and 10 months (Paridaens et al., 2008).

 Chemotherapy regimens that are prescribed in hormone receptor-positive patients includes
 microtubule inhibitors (including taxanes and vinca alkaloids), anthracyclines, gemcitabine,
 cyclophosphamide and capecitabine. But endocrinal therapy is preferred as long as the patient
 is not in visceral crisis (Cardoso et al., 2017).

 Recently new drugs that increased progression free survival (PFS) has been approved in the
 treatment of HR +ve metastatic breast cancer (MBC) as fulvastrant (Selective estrogen
 receptor modulator) (Ellis et al., 2015) and palbocilib (Ck4/6 inhibitor) (Finn et al., 2015)
 as first line and eveirolimus (mTor inhibitor)(Pritchard et al., 2012) as second line.

 The optimum sequence of endocrinal treatment and chemotherapy has not been fully clarified,
 It is of great importance to bear in mind that the goal of treatment in recurrent and
 metastatic breast cancer is extending the progression free survival (PFS) and sustaining a
 good quality of life (Cardoso et al., 2017).

 A retrospective study by Shankar et al. that compared between combination of capecitabine and
 aromatase inhibitor (AI) versus capecitabine alone versus aromatase inhibitor alone showed
 that the median PFS of first-line treatment was significantly better for the combination with
 PFS 21 months vs 8.0 months for capecitabine and 15.0 months for AI. For second-line
 treatment, the PFS was longer in the combination compared with capecitabine and Al groups (18
 months vs. 5.0 months vs. 11.0 months, respectively) (Shankar et al., 2015).

 Alvarado et al, compared combination aromatase inhibitor plus capecitabine versus
 capecitabine alone versus aromatase inhibitor alone. The median PFS of first-line treatment
 was significantly better for the combination (PFS not-reached for combination vs.3.0 m for
 capecitabine and 13.0 m for AI, p<0.0001). For second-line treatment, the PFS was longer in
 the combination compared to capecitabine and AI (PFS not reached vs. 6.0 m vs.13.0 m,
 respectively, p=0-041) (Alvarado et al., 2012).

 In China a Phase II trial assessed the use of of metronomic oral capecitabine therapy
 combined with aromatase inhibitors in postmenopausal metastatic and recurrent breast cancer
 resistant to first-line aromataseinhibitors and the results showed overall Response Rate
 (ORR) 70.5% and median PFS 9.57 months (L. Jian-wei et al., 2015). Lee S. Schwartzberg
 conducted a phase II trial which results showed that fulvastrant with metronomic capecitabine
 for women with HR-Positive, HER2-Negative MBC has Median PFS was 14.98 months (Schwartzberg
 et al., 2014).

 Capecitabine; being cheaper and more available in economically disadvantaged countries
 together with the promising results of the previous retrospective trial by Shankar et al and
 the prospective trial by Alvarado Miranda et al ; further confirmation of such results by a
 prospective randomized clinical trial is crucial. Currently a phase III trial under the title
 of "Metronomic Capecitabine Plus Aromatase Inhibitor for First Line Treatment in HR(+),
 Her2(-) Metastatic Breast Cancer" with the primary results expected to be published on 2021
 (Sun Yat-sen University, 2016).
Inclusion Criteria:

 1. Adult women with locoregionally recurrent or metastatic disease not amenable to
 curative therapy

 2. Eastern Cooperative Oncology Group (ECOG) 0-2

 3. Hormone receptor positive

 4. No prior systemic anti-cancer therapy for advanced ER+ disease ( hormonal therapy)

 5. Measurable disease defined by revised RECIST criteria (version 1.1), or bone-only
 disease

 6. normal laboratory values

 7. Postmenopausal or premenopausal with oophorectomy (medical or surgical).

 Exclusion Criteria:

 1. Patients with advanced, symptomatic, visceral spread that are at risk of life
 threatening complication in the short term

 2. Prior (neo) adjuvant treatment with same aromatase inhibitor type with DFI =< 12
 months from completion of treatment.

 3. Known uncontrolled or symptomatic central nervous system metastases

 4. Second primary malignancy

 5. Serious uncontrolled intercurrent infections or intercurrent medical or psychiatric
 illness

 6. unable to swallow tablets, or malabsorption patients.

 7. unwilling or unable to comply with study protocol or unable to meet the follow up.

 8. patients who researchers considered were not suitable to participate.