1. Susman, Ed

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In a prospective clinical trial, women who presented with metastatic breast cancer did not have any additional survival by undergoing treatment to surgically remove the primary tumor. That was the conclusion of a study reported at the CTRC-AACR San Antonio Breast Cancer Symposium.

RAJENDRA BADWE, MD. ... - Click to enlarge in new windowRAJENDRA BADWE, MD. RAJENDRA BADWE, MD: "I'm sure a lot of oncologists who believe in conventional wisdom and don't provide locoregional treatment will feel a lot more comfortable looking at these results. As for those who have changed practice based on the retrospective study history, they would have to rethink."

"The clinical conclusion would be that locoregional treatment of the primary tumor in women presenting with metastatic breast cancer did not result in any overall survival benefit and hence should not be offered as routine practice," said Rajendra Badwe, MD, Director of Tata Memorial Hospital in Mumbai, India.


In a news conference at the meeting, he suggested that the study, which was funded by the hospital and the Department of Atomic Energy Clinical Trial Center in India, might settle the ongoing controversy over whether removal of the primary tumor through surgery and radiation therapy after courses of chemotherapy is the right thing to do. His position, based on the study outcome, is to forego the attempt at locoregional-with the possible exception of treating fungating or painful masses.


When the researchers analyzed overall survival, the primary endpoint of the study, "there was nothing much to look at," he said. The overall survival rate at five years was 20.5 percent among women who did not receive the extensive surgery and radiation compared with 19.2 percent of those who did receive locoregional treatment. That translated to a four percent relative increased risk with the more extensive therapy, but the difference failed to achieve statistical significance (P=0.79).


In an extensive subgroup analysis that included menopausal status, metastatic site, number of metastases, hormonal status, and HER2-positive status, no group could be found that was significantly associated with the minor increase in mortality observed with extensive locoregional treatment, he said. "None of these variables showed any significant differences whether surgery was performed or not. Uniformly, there was no difference in any subsets.


"The conventional wisdom believes that these women should have surgeries only if there is fungation or bleeding and they are not offered treatment for locoregional disease," he said, noting that his results support this strategy.


Conflicting Earlier Data, but Retrospective Data

The waters have been muddied, however, by other studies, he continued. "In the past few decades there have been many studies, all of them retrospective, at an institutional or registry level, that have looked at the survival of patients who have had surgery, showing a 35 percent reduction in death in patients who have had surgical intervention. I must warn, though, that all these studies are retrospective and are fraught with selection bias."


On the other hand, animal experiments indicate that removal of the primary tumor appeared to enhance growth in the secondary tumors. "So the house was divided, and hence we did this trial to assess the effect of removal of the primary tumor and axillary lymph nodes."


The researchers enrolled about 400 women in the trial from 2005 to 2013. After diagnosis of metastatic breast cancer, all the participants underwent chemotherapy with anthracyclines or anthracyclines followed by taxanes. The women were evaluated after six to eight cycles of treatment, and those who had a partial or complete response were randomized to receive either extensive locoregional treatment or no treatment to the primary tumor.


Badwe and his colleagues randomized 350 women, with 173 assigned to locoregional treatment. These women underwent breast-conserving therapy, depending on the location of the tumor, or had a modified mastectomy. They all also underwent complete axillary dissection. Surgery was followed by radiation to the chest wall as well as the peripheral glandular area; a second group of 177 women did not receive locoregional therapies.


Women who were pre-menopausal and hormone sensitive also underwent ovarian ablation and were continued on tamoxifen. Women who were post-menopausal received aromatase inhibitors.


During the median follow-up of 17 months, there were 218 deaths-11 in the locoregional treatment arm and 107 in the no-treatment arm.


While there was no statistical significance in overall survival, Badwe admitted that researchers were perplexed by finding a "huge difference" in locoregional disease control among women who underwent surgery. The risk of experiencing locoregional disease progression was reduced by 84% (P<0.01).


Although locoregional control favored surgery, the risk of distant progression favored the group of women who did not have surgery. Distant progression-free survival was achieved by 47.5 percent of the women who did not undergo surgery, compared with 28.3 percent of those who did (P=0.01).


"We saw a huge difference in local control, but that did not translate into overall survival benefit. That begs the question, especially since the distant progression-free survival was diametrically in the opposite direction. There was a 43 percent excess progression among the women who had surgical intervention.


'Kind of a Trade Off'

"There was a kind of trade off: While there was a greater than 80 percent reduction in locoregional control, the same subgroup had a rapid distant progression of disease that cancelled out all the benefit of locoregional control."


Eighteen women in the non-surgery group eventually did have surgery due to fungating tumors or because of pain in the breast caused by the tumor-that represented about 10 percent of the women in the non-surgery group. "It shows that not all women progress to fungating or infected tumors," he said. "Only 10 percent of these women needed surgery for quality-of-life issues.


About five to 20 percent of women with breast cancer present with metastatic disease, he said. "In the U.S. about five to 10 percent of women do, and that number has not changed over the last decade in this country or in India." In India, he noted, about 10 to 15 percent present with metastatic disease.


"I'm sure a lot of oncologists who believe in conventional wisdom and don't provide locoregional treatment will feel a lot more comfortable looking at these results," he said. "As for those who have changed practice based on the retrospective study history, they would have to rethink."


Comments from Kent Osborne

In commenting on the study as moderator of the news briefing, Kent Osborne, MD, Co-director of the Symposium and Director of the Dan L. Dunkin Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, said, "There are two issues for women who present with metastatic disease: One, can we do something to improve their survival. We have new drugs that sometimes can prolong survival in individual patients, but overall we don't do well in patients with metastatic disease.


"The other issue is what do you do about the tumor in the breast, and there are two issues there. In some patients especially those in their older years, the patient would have a terrible infected, fungating, bleeding mass on the chest wall, and that is a terrible way to die of a disease. In many of these cases, mastectomy was done to give palliation.


"It appeared that this surgery improved survival and begged for a trial such as this one, which shows that surgery is not helpful. It is not to say we should not do mastectomies in the appropriate patient, but the trial argues against doing surgery in all patients as a routine treatment, and perhaps only in those patients in whom there is going to be a cosmetic problem on the chest wall with a large infected mass," he said.


Increased Risk of Metastases

Badwe suggested that his study results indicate that surgical removal of the primary tumors "appears to confer a growth advantage on metastatic disease." He said that for the first time researchers have observed that the observations reported in animal studies 30 to 40 years ago have now been observed in humans.


He speculated that surgery on the primary tumor might activate growth factors that enhance secondary tumor growth. In addition, the primary tumor may produce inhibitory factors that slow the growth of the secondary tumors and that inhibition disappears once the primary tumor is excised. And, surgery itself might in some way create new disease. "Exactly what factors in the blood or in the tumor increase the growth of the metastases is still not known."


iPad Extra!

Watch on the iPad edition of this issue as Rajendra Badwe elaborates on the study in an interview with OT reporter Dan Keller.


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