Consider the ups and downs of postmastectomy radiation. It starred in one of the first randomized clinical trials in the 1940s, which compared it to no postsurgical treatment for breast cancer and found an improvement in local and regional control of the disease. Confirmed in that role by numerous other studies, it held the status of standard treatment for several decades.
Then in the 1980s, the pendulum began to swing away from radiation after mastectomy. One problem was that it did not seem to affect survival. Another was growing evidence that radiation to the left side of the chest damaged the heart, erasing any survival advantage that may have existed. Third, and perhaps most important, the systemic approach to preventing breast cancer recurrence chemotherapy was then coming into its own.
"The belief was that if chemotherapy can deal with distant recurrences, then it can deal with locoregional recurrences and you don't need radiation," said Barbara Fowble, M.D., of the Fox Chase Cancer Center, Philadelphia.
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It owes its comeback primarily to two articles in The New England Journal of Medicine in 1997 reporting that postmastectomy radiation had, for the first time, extended survival in randomized trials. The studies, one in Denmark and one in British Columbia, have fueled an ongoing debate over the applicability of the data. But even as the controversy simmers, the practice pendulum seems to be swinging back in favor of radiation, along with chemotherapy, after mastectomy.
Until the two studies appeared, postmastectomy radiation was being used only in some institutions and only in women with four or more positive nodes. The studies challenged current thinking in the United States, said Lori Pierce, M.D., of the University of Michigan, not only because they showed that radiation could affect survival but also because they showed that the survival benefits extended even to women with one to three positive nodes.
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The National Comprehensive Cancer Network also reconsidered its position on postmastectomy radiation in the wake of the two studies. Where the NCCN once said that radiation should be considered for women with four or more nodes, it now says, like ASTRO, that radiation should be standard; and where there was no mention of radiation for women with fewer nodes, there is now the recommendation that it be considered.
Consensus on the NCCN guideline was not reached easily, according to the chair of the breast cancer committee, Robert Carlson, M.D., of Stanford University, Palo Alto, Calif. Some members argued that postmastectomy radiation should be standard in women with one to three nodes not just considered.
Crux of Debate
It is this subgroup, patients with one to three positive nodes, who are at the crux of the debate. While some think there is enough data to justify irradiating these patients, others urge caution. "The pendulum is swinging back, but I don't think it should swing all the way back to the '40s when everybody got radiation," said Fowble, who presented her view of the controversy at this year's annual meeting of the American Society of Clinical Oncology. "We have to see who needs it."
Fowble and others are wary of the Danish and British Columbia data for several reasons. First, the control groups in both studies those who did not receive radiation had unexpectedly high rates of local recurrence among women with one to three nodes. The rates were 30% in the Danish study and 33% in the British Columbia study.
"My inclination is to say, gee, [the Danish and British Columbia data are] so different from what we see in the United States let's not jump before we know what's going on here," said Fowble.
By contrast, the usual recurrence rates for comparable patients in the United States are in the range of 5% to 15%. In a recent study of risk factors for local and regional recurrence led by Abram Recht, M.D., Beth Israel Deaconess Medical Center, Boston, the recurrence rate for women with one to three nodes who did not receive radiation was 12.9%.
The high recurrence rates in the Danish and British Columbia studies suggest that patients in these trials were under-diagnosed, i.e., they actually had more positive nodes than were identified. Supporting this view is the observation that relatively few nodes were removed and examined in these two studies. The median numbers were seven in the Danish study and 11 in the British Columbia study, while the U.S. standard is in the range of 10 to 15. If these patients were under-diagnosed, it could account for their high recurrence rate and thus the impact of radiation therapy on survival.
A second reason to treat the Danish and British Columbia data with caution, Fowble said, is that they were using an older chemotherapy regimen (cyclophosphamide, methotrexate, and fluorouracil). With newer regimens the risk of local and regional recurrence and thus the need for radiation may be quite different.
Not so Easy
Others argue that it is not so easy to explain away the Danish and British Columbia data. Robert Kuske, M.D., of the Ochsner Center for Radiation Oncology, New Orleans, who shared the ASCO dais with Fowble and Recht, pointed out that the higher survival rates were not limited to patients with few removed nodes. Those in the Danish study who had 10 or more nodes removed also appeared to benefit from radiation. In addition, Kuske emphasized, huge improvements in radiation technique have minimized the risk of cardiac damage, removing some of the risks of postmastectomy radiation.
The size of the survival benefit in the two studies also makes it difficult to discount the findings, say some experts. "The survival impact was in the range seen with chemotherapy," noted Nicholas Robert, M.D., a medical oncologist in Northern Virginia and one of six members of the ASTRO consensus panel. "That is what is fueling the change."
Robert does not think these data are strong enough to override all concerns about the studies' limitations and recommend radiation in women with one to three nodes. "But they are strong enough to make it a question on the table," he said.
That question will be taken up by investigators now planning a large U.S. trial, due open early next year. The trial will enroll about 2,500 patients with one to three positive nodes who will be randomized to radiation therapy or no radiation therapy after mastectomy and chemotherapy. Unlike the Danish and British Columbia studies, this one will include postmenopausal women. That means the results will be applicable to a large group of patients, said Pierce, the principal investigator. The protocol will require use of sophisticated radiological techniques to protect the heart, including computerized tomography-assisted treatment planning.
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