Trial Information

A Randomized Trial To Assess The Impact Of Loco-Regional Treatment On Survival Of Patients With Metastatic Breast Cancer At First Presentation

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.

VEGF[5], 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
SMAC/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 ER/ PgR status.

B. Staging:

- Liver function tests

- 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 (SGOT/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 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 CRFs.

END POINT:

Primary: 1. Time to progression (symptomatic, confirmed by investigations). 2. Death.
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.