Ignite Creation Date:
2024-05-05 @ 11:58 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00193778
Status:
COMPLETED
Last Update Posted:
2020-10-08
First Post:
2005-09-12
Brief Title:
Assessing Impact of Loco-regional Treatment on Survival in Metastatic Breast Cancer at Presentation
Sponsor:
Tata Memorial Hospital
Organization:
Tata Memorial Hospital
Study Overview
Official Title:
A Randomized Trial To Assess The Impact Of Loco-Regional Treatment On Survival Of Patients With Metastatic Breast Cancer At First Presentation
Status:
COMPLETED
Status Verified Date:
2020-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 andor bleeding
Studies in metastatic renal cell carcinoma have shown that removal of primary tumor can cause disappearance of metastases 1 and improve survival23 The exact mechanism of this phenomenon is not understood Although immunologic mechanisms have been suggested these remain largely unproven1 On the contrary metastases autonomy hypothesis on animal models suggests that removal of primary tumor renders autonomy to metastases which start growing rapidly4 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 VEGF5 basic fibroblast growth factor bFGF6 are some of the angiogenic and proliferative factors which stimulate tumor metastasis growth Angiostatin7 and Endostatin8 are the some of the inhibitors of angiogenesis It is the balance between angiogenic factors and anti-angiogenic factors that determines the tumormetastases growth7 Lot of ongoing research9 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 days4 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 ie surgery modified radical mastectomyMRM 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 mgm2 Adriamycin 60 mgm2 5- Fluoro-Uracil 600 mgm2
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 eg 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 25mg OD Anastrozole 10mg 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 histologiesmedullary 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 internalexternal 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
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 andor bleeding
Studies in metastatic renal cell carcinoma have shown that removal of primary tumor can cause disappearance of metastases 1 and improve survival23 The exact mechanism of this phenomenon is not understood Although immunologic mechanisms have been suggested these remain largely unproven1 On the contrary metastases autonomy hypothesis on animal models suggests that removal of primary tumor renders autonomy to metastases which start growing rapidly4 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 VEGF5 basic fibroblast growth factor bFGF6 are some of the angiogenic and proliferative factors which stimulate tumor metastasis growth Angiostatin7 and Endostatin8 are the some of the inhibitors of angiogenesis It is the balance between angiogenic factors and anti-angiogenic factors that determines the tumormetastases growth7 Lot of ongoing research9 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 days4 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 ie surgery modified radical mastectomyMRM 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 mgm2 Adriamycin 60 mgm2 5- Fluoro-Uracil 600 mgm2
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 eg 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 25mg OD Anastrozole 10mg 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 histologiesmedullary 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 internalexternal 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None