Medicine Matters oncology

So the data presented at ASCO this year in 2020 is from a trial conducted by the ECOG-ACRIN network cooperative group with collaboration from other US and Canadian cooperative groups. The major question was, should we be offering loco- regional treatment in women who are initially either responding to systemic therapy or stable on systemic therapy? And the answer to that question, of course, is that locoregional therapy does not offer a survival advantage.

So over the past 15 years or so, this has been a very controversial area. And many physicians and patients, actually, many patients found this intuitively attractive. So the patients were actually very interested in the idea of seeking loco- regional therapy for their intact primary tumor with the expectation that it may improve their survival. And I think we have a clear answer to that question now because our trial shows absolutely no difference with 21st century standard of care systemic therapy being used appropriately according to guidelines. It offers no advantage with the use of locoregional therapy.

Our trial is in agreement with the previous trial published by the Tata Memorial group in Mumbai, India. They had a much more advanced group of patients with heavier metastatic burden. And their systemic therapy was according to Indian standards of care. And many of their HER2 patients did not receive HER2-directed therapy. So there were some questions about whether an improve-- a more aggressive, more contemporary systemic therapy would lead to a different result than the Indian trial, which showed no advantage in survival with the use of locoregional treatment.

So the results of our trial in a contemporary resource-rich setting are the same as the results of the Indian trial, which was conducted in a more resource-limited setting. And then in between these two trials there is, of course, a trial from the Turkish federation that also tested the same question. Their design was a little different in that they enrolled women with stage IV disease and then randomized them immediately so that they were not filtered by the use of initial systemic therapy and they didn't-- they weren't able to exclude women who would have progressed on systemic therapy because of this earlier randomization.

So that trial somewhat surprisingly did show an advantage of five years. They have a hazard ratio of about 0.7 with the use of early locoregional treatment. And their absolute overall survival difference at five years is 17%, a very large difference.

And it's not quite clear why the results are different because, if one thinks about the delivery of systemic therapy, the Turkish setting is a little more similar to the US and Canadian setting in that they were able to use HER2-directed therapy. Their trial size was about similar. So they didn't have an advantage in terms of statistical power or numbers. But they did see this difference in survival.

Their primary endpoint, of course, was at three years survival. They didn't find a difference for three years. But when they reanalyzed at five years, they did see an advantage.

It's worth noting, though, that they did not stratify for the major subtypes of breast cancer. And they did have some imbalance in the randomization arm. So again, of the three trials that have been reported so far, the Indian and the US/ Canadian trial do not show an advantage whereas the Turkish trial did. So I think, looking at the weight of the evidence, one can say with confidence to patients who may be seeking locoregional treatment in the expectation of improved survival that there is really no good evidence to support that, that the weight of the evidence is against the use of locoregional treatment for women with stage IV breast cancer.

That doesn't, of course, apply to the use of palliative treatment for women whose local disease is progressing. And that does happen occasionally, where the systemic disease is well controlled with systemic therapy but the local tumor shows evidence of progression. So in that setting or if symptoms appear, there are some quality-of-life concerns and local control concern.

And in a setting where systemic disease is well controlled, local disease is progressing, I think one could make an argument for the use of locoregional therapy. But that would not apply early in the course of management of the systemic stage IV disease. It would only apply in selected women whose local disease are showing signs of progression.