Assessing Impact of Loco-regional Treatment on Survival in Metastatic Breast Cancer at Presentation
Condition: Cancer of the Breast
MeSH terms: Breast Neoplasms
Study type: Interventional

Summary: 
      Traditionally metastatic breast cancer patients are not offered loco-regional treatment
      except in cases of fungation or bleeding. However, scientific evidence for such omission of
      loco-regional treatment in metastatic breast cancer patients is lacking. On one hand, studies
      have shown that removal of primary tumor at times leads to complete disappearance of
      metastases and improvement in survival in renal cell carcinoma patients. However, such
      studies have never been performed in other solid tumors. On the other hand, there is a strong
      body of evidence in experimental settings that show that removal of primary tumor allows
      growth of metastasis. There is lack of similar data in humans in clinical settings. Offering
      loco-regional treatment in metastatic breast cancer patients in a setting of randomized
      controlled trial will help in improving survival of such patients and understanding the
      natural history of breast cancer.
    

Detailed description: 
      PRESENT KNOWLEDGE:

      Loco-regional treatment should not be attempted in metastatic breast cancer patients is a
      traditional teaching, which lacks scientific basis. Omission of loco-regional treatment can
      not be part of standard care if the scientific evidence is inadequate. Today such a treatment
      is offered for fungation and/or bleeding.

      Studies in metastatic renal cell carcinoma have shown that removal of primary tumor can cause
      disappearance of metastases [1] and improve survival[2,3]. The exact mechanism of this
      phenomenon is not understood. Although immunologic mechanisms have been suggested, these
      remain largely unproven.[1] On the contrary, metastases autonomy hypothesis on animal models
      suggests that removal of primary tumor renders autonomy to metastases, which start growing
      rapidly.[4] The suggested mechanism for this is anti-angiogenic/ angiostatic activity of the
      primary tumor. However, such studies have never been performed in human subjects.

      Which hypothesis is true? What does removal of primary tumor cause - suppression or
      stimulation of growth of metastases? Whether such suppression or stimulation affects
      survival? These are few questions, which need to be answered to improve our understanding of
      natural history of breast cancer. vascular endothelial growth factor (VEGF)[5], basic
      fibroblast growth factor (bFGF)[6] are some of the angiogenic and proliferative factors which
      stimulate tumor/ metastasis growth. Angiostatin[7] and Endostatin[8] are the some of the
      inhibitors of angiogenesis. It is the balance between angiogenic factors and anti-angiogenic
      factors that determines the tumor/metastases growth[7]. Lot of ongoing research[9] is focused
      on administration of Angiostatin and Endostatin to tilt this balance in favor of
      anti-angiogenesis. Does removal of the primary tumor change this balance? And what impact
      this change in balance (if any) have on survival? These questions have not been answered by
      in-vivo studies in humans. Demonstration of such effects or absence of these effects can help
      us in refining our therapeutic targets in metastatic patients.

      There is dearth of reliable data on change in the levels of angiogenic, proliferative growth
      factors and anti-angiogenic factors in relation to the time after removal of primary. Removal
      of primary tumor resulted in growth of metastases in animal experiments in five days[4] and
      the metastases tripled in size by thirteenth day. Hence, we decide to measure levels of these
      factors at the end of one week following surgery and at the end of three months.

      This study aims at:

      Firstly, assessing impact of loco-regional treatment on survival in metastatic breast cancer
      patients.

      Secondly, understanding the mechanism of suppression/ stimulation of growth of the metastases
      through measurement of angiogenic, proliferative growth factors and anti-angiogenic factors
      before and after intervention.

      TRIAL DESIGN:

      Patients with metastatic breast cancer diagnosed by incision biopsy and staging
      investigations will undergo six cycles of anthracycline-based chemotherapy. At the end of
      chemotherapy, these patients will be randomized into two groups. First group will receive
      standard loco-regional treatment i.e. surgery (modified radical mastectomy(MRM)/ Simple
      Mastectomy with Axillary Clearance (SMAC)/ Breast Conservation Therapy (BCT) +/- radiotherapy
      (depending on type of surgery performed or histopathology report). Second group will not
      receive any loco-regional treatment.

      INVESTIGATIONS:

      A. Diagnostic: Incision biopsy for primary diagnosis and estrogen receptor (ER)/ progesterone
      receptor (PgR) status.

      B. Staging:

        -  Liver function tests

        -  Chest X-ray & USG - Abdomen & pelvis &/ CECT chest with Upper Abdomen

        -  Bone scan with relevant x-ray skeletal survey (MRI in doubtful cases)

      ELIGIBILITY:

      Inclusion criteria:

        1. Metastatic breast cancer patients with expected survival of at least one year

        2. Age 21-65 years

      Exclusion criteria:

        1. Patients who are not fit to receive anthracycline based chemotherapy.

        2. More than two visceral organ involvement.

        3. Multiple liver metastases with deranged liver function tests serum glutamic oxaloacetic
           transaminase (SGOT) / serum glutamic-pyruvic transaminase (SGPT) more than four times
           the upper normal limit).

        4. Locally static or progressive disease or systemically progressive disease as shown by
           repeat staging investigations guided by worsening symptoms.

        5. Ulceration/ fungation/ bleeding after completion of chemotherapy, which mandates
           surgery.

        6. Expected survival of less than six months after completion of chemotherapy.

        7. Unfit for anesthesia due to metastatic disease.

      CONSENT AND RANDOMIZATION:

      Computerized randomization will be carried out at the central office after confirmation of
      eligibility and obtaining informed written consent. Randomization will be stratified by

        1. Visceral or bone and/ or soft tissue metastasis.

        2. Less than or equal to 3, or more than three metastases.

        3. Hormone responsive or non-responsive tumor.

      TRIAL SIZE AND ACCRUAL:

      Breast cancer patients who have metastatic disease at presentation have a median survival of
      eighteen months. Detection of six-month improvement in this survival with 95% confidence and
      80% power by a two tailed analysis will require a minimum of 350 patients.

      METHODOLOGY:

        1. All eligible patients will be provisionally marked for the trial.

        2. Number and sites of all the metastases will be documented along with the size.

        3. Patients will receive maximum of six cycles of Cyclophosphamide (600 mg/m2), Adriamycin
           (60 mg/m2), 5- Fluoro-Uracil (600 mg/m2).

        4. Patients will be reassessed at the end of chemotherapy (approximately five months
           later). Staging investigations viz. CECT thorax and upper abdomen (in cases of visceral
           metastasis) and relevant X-rays will be repeated. All eligible patients will be
           randomized into two groups (stratified randomization). First group will undergo standard
           loco-regional treatment (surgery followed by radiotherapy depending on histopathology
           report or type of surgery performed e.g. BCT) and surgical oophorectomy (at the time of
           surgery) followed by hormone therapy (in ER and/ or PgR positive pre-menopausal
           patients). Postmenopausal patients will receive hormone therapy. Second group will be
           started on hormone therapy (all ER and/ or PgR positive and/ or postmenopausal
           patients). Hormone therapy will be in the form of Aromatase inhibitors (Letrozole 2.5mg
           OD/ Anastrozole 1.0mg OD)

        5. All patients in loco-regional treatment group will have two or three blood samples
           (10-cc blood in plain bulbs) collected. These samples will be used for estimation of
           VEGF, bFGF, Angiostatin and Endostatin by ELISA.

           Sample 1: A day prior to surgery. Sample 2: Seventh post operative day. Sample 3: Three
           months after the surgery.

        6. The metastases will be reassessed after twelve weeks of surgery for any change in size
           and number by repeat staging investigations viz. CECT thorax and upper abdomen (in cases
           of visceral metastasis) and relevant X-rays and again on symptomatic progression.

      Patients with symptomatic bony metastases will in addition receive local radiotherapy
      (wherever indicated) and/ or bisphosphonates (wherever indicated).

      Patients in both the arms will undergo metastasectomy wherever indicated.

      PATHOLOGY: Pathological tumor size, number of axillary lymph nodes dissected and number
      positive for metastasis, histological type of the primary tumour (infiltrating duct carcinoma
      with standard grades, infiltrating lobular carcinoma, other rare histologies[medullary,
      papillary, colloid etc.]), presence or absence of lymphatic, vascular and peri-neural
      invasion should be noted in all patients. Estimation of other biological markers ER, PgR is
      mandatory. Entries will be made in case report forms (CRFs).

      END POINT:

      Primary: 1. Overall survival (time to death) 2. Progression free survival

      Secondary:

      Changes in VEGF, bFGF, Angiostatin and Endostatin.

      DATA COLLECTION, QUALITY CONTROL AND ANALYSIS:

      Data collection will be carried out by individual clinician on prescribed forms:
      Pre-randomization form, primary data sheet, and pathology information. At least 20% of the
      data will be cross-checked by internal/external review. The trial centre data manager with
      the help of individual clinician will maintain completeness of data but the latter will be
      responsible for the correctness of information. All forms will be maintained in duplicate at
      the central trial office.

      Data monitoring committee will periodically review the trial. Univariate comparison between
      randomization arms will be carried out using chi-squared test.
    

Intervention name(s): Surgery for breast cancer; No Loco-regional treatment
Intervention type(s): Procedure; Other
Intervention description(s): This group will receive standard loco-regional treatment i.e. surgery (modified radical mastectomy (MRM)/ Simple SMAC/BCT) +/- radiotherapy; This group will not receive any loco-regional treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Metastatic breast cancer; Locoregional treatment; Survival