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. 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.