Early Local Therapy vs Systemic Therapy Alone for De Novo Stage IV Breast Cancer

PracticeUpdate: One of the plenary sessions provides data on the role of local therapy for metastatic breast cancer. Traditionally, what has been the approach to dealing with primary breast tumors among patients presenting with metastatic disease?

Dr. Anderson: The history of how we manage breast cancer actually goes back to the 1890s, with the description of the radical mastectomy. At that time, the thinking was to hurry up and operate and get around the disease before it can metastasize. That thinking was based on anatomy, the idea that if we understand the anatomy and can go beyond the anatomy, that's how we will save lives.

The question of how to manage breast cancer when it's already metastatic has been a pervasive question since that time. We've been making a transition in understanding that instead of the disease being based upon anatomy, progression being based on anatomy, it's based on biology, and that is why the systemic therapies are so important to what we do.

But this left this persistent question: if we already have metastatic disease, does locoregional therapy surgery with radiation, does it prolong life? Does it make it less likely that someone will die of their disease? This question has been very difficult to answer because of the challenges of getting high-quality randomized trials free of bias.

There was a very important study…the ECOG-ACRIN E2108 trial, in which women who had presented with metastatic disease, so de novo stage IV disease, were after a period of time of having stable, locoregional disease for a period of 4 to 6 months, 256 were randomized to either early locoregional therapy, following the same principles that we would follow in the absence of metastatic disease, or they were kept on systemic therapy and only underwent a surgery if they had challenges with locoregional control.

This randomized trial was reported by Dr. Seema Khan from Northwestern University, and then a commentary was provided by Dr. Julia White. Dr. Khan is a surgeon; Dr. White is a radiation oncologist at Ohio State. What this randomized trial showed us was there is no survival benefit to performing the routine use of locoregional therapy in the setting of de novo stage IV disease. Women did not live longer because they had their surgeries provided earlier rather than later. This really is a very important question to answer because it means that when we talk to patients about locoregional management, and we talk about going to surgery when we already know about stage IV disease, we cannot suggest to those women that they will be less likely to die of their breast cancer on the basis of that therapy.

On the other hand, what this trial also showed was that locoregional failure, progression of disease locally, either in the breast or in the nodes, was a significant issue. So, among the women who were randomized to systemic therapy, 25% ultimately had locoregional issues that required some type of locoregional management, one-quarter versus only 10% in those who had had the early locoregional therapy.

Our trial showed us two things. It showed us that we do not make women live longer by virtue of doing this intervention with locoregional therapy. It should not be routine, but on the other hand, locoregional control was a problem in one out of four. For that reason, locoregional therapy continues to play a role, it's just in selected patients rather than on a routine basis.

Reflecting on this trial, this is actually not new information to us. The idea that locoregional control is a different topic from overall survival, we've actually known this since the NSABP B-O6 trial showed us that breast conservation works…In that trial, there was a group who had lumpectomy alone and had very significant failure rates, up to 40% at 12 years. That is the reason that we continue to do radiation after lumpectomy because of those high, locoregional failure rates.

It did not translate to an overall survival difference in B-O6. Actually, we're seeing the same pattern, this information that this is a biological issue based upon systemic therapy is not new. But it also speaks to the point about overall mortality. Survival is not the only important endpoint. Locoregional control is a significant endpoint that we have to pay attention to.

Now, in this randomized trial, there were quality-of-life questionnaires that were administered, and they actually did not see an improvement overall in quality of life. So, we can't say, "Oh, we've got a randomized trial that says the quality of life on average is improved."

But clearly, that locoregional control issue is an independent topic. We have to consider it separately from the overall survival issues of are we managing the disease adequately with locoregional control in ways that are tolerable for our patients and optimize their outcome, not just in terms of overall survival, but also control of disease in the breast and the axillary nodes.