For Node-Positive Breast Cancer, Axillary Radiation Is Best

Kate Johnson

June 06, 2013

CHICAGO, Illinois — Radiotherapy is a better option than surgical dissection for women with breast cancer and a positive sentinel lymph node, according to an international multicenter phase 3 trial.

In fact, axillary lymph node dissection (ALND) was associated with twice the rate of lymphedema as axillary radiotherapy, with no better locoregional control and fewer adverse effects, in the European Organization for Research and Treatment of Cancer (EORTC) AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery?) trial.

The results were presented here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

"We shifted from mastectomy to breast conservation, and now we will shift from complete axillary dissection to axillary-conserving strategies," study author Emiel Rutgers, MD, PhD, surgical oncologist at the Netherlands Cancer Institute in Amsterdam, said during a press conference.

Impact on Clinical Practice

However, experts in the United States differ on how the findings will affect clinical practice.

"I suspect it's going to change practice at my institution," said Andrew Seidman, MD, a medical oncologist from the Memorial Sloan-Kettering Cancer Center in New York City.

"In the sentinel node era, we learned from melanoma that less can be more. Now we've learned that this is true in breast cancer — we can avoid sometimes disfiguring and painful surgery," he noted.

However, a shift away from ALND is already well underway in the United States, according to 2 experts. They say that the real impact of the study findings will likely be on decisions about radiation therapy.

 
We've just added fuel to the fire. Dr. Anne Wallace
 

"We've just added fuel to the fire. I think women are going to be overtreated with radiation now," said Anne Wallace, MD, surgical oncologist and director of the breast care unit at the University of California, San Diego (UCSD) Moores Cancer Center, and chief of plastic surgery at the UCSD Health System. We believe that less is more in breast cancer, but we don't want to trade more surgery for more radiation, she told Medscape Medical News.

The trial results resolve a surgical issue but leave a radiotherapy question mark, said Abram Recht, MD, professor of radiation oncology at Harvard Medical School, and deputy chief in the Department of Radiation Oncology at the Beth Israel Deaconess Medical Center in Boston, Massachusetts. "The AMAROS trial does not really tell us whether axillary radiotherapy is better than breast radiotherapy with regard to overall outcome, so it cannot tell us that it should be the new standard."

Study Details

The AMAROS trial involved patients with cT1-2N0 breast cancer up to 5 cm and clinically node-negative axilla who were undergoing either breast conservation or mastectomy with sentinel lymph node mapping.

Of the patients with positive lymph nodes, 744 went on to receive ALND and 681 received axillary radiotherapy.

Radiotherapy (50 Gy in 25 fractions of 2 Gy, 5 days a week) was started within 12 weeks of surgery, and directed at 3 levels of the axilla and the medial part of the supraclavicular fossa, Dr. Rutgers explained. Levels I and II of the axilla were mandatory and level III was optional.

There were no significant differences in between the radiotherapy and surgery groups at baseline. Median age was 55 to 56 years, and 38% to 42% of the patients were premenopausal. Median tumor size was 17 to 18 mm, and 75% of patients had grade 2 or 3 cancer.

In the cohort, 82% underwent breast conservation and the remainder underwent mastectomy; 90% received systemic treatments. A median of 2 sentinel nodes were removed from each woman.

For patients who received axillary clearance, the sentinel node was the only positive node in 67%; 33% had further node involvement and 8% had 4 or more positive nodes.

After 5 years of follow-up, the axillary recurrence rate was "extremely low" in the surgery and radiotherapy groups (0.54% vs 1.03%), Dr. Rutgers reported.

Because "this was far below what we anticipated, the trial was underpowered for a noninferiority comparison," he explained.

There were no significant differences between the surgery and radiotherapy groups in disease-free survival (86.9% vs 82.7%; P = .1788) or overall survival (93.3% vs 92.5%; P = .3386).

However, 5 years after therapy, the rate of lymphedema in the surgery group was twice that of the radiotherapy group (28% vs 14%).

"The AMAROS trial provides very important evidence that the kind of regional nodal treatment used after a positive sentinel node biopsy will not substantially affect the risk for subsequent regional nodal failure, rates of metastasis-free breast-cancer-specific, or overall survival in most patients," Dr. Recht told Medscape Medical News.

He explained that a more important question than whether to choose radiotherapy is which type to choose.

"Is axillary radiotherapy better at preventing regional nodal failure than just irradiating the breast, which includes the lower portion of the axilla in many individuals?" he asked.

Dr. Recht said that previous studies that compared breast radiotherapy with ALND — such as the American College of Surgeons Oncology Group Z0011 trial (Ann Surg. 2010;252:426-432 and JAMA. 2011;305:569-575), as reported by Medscape Medical News, and the International Breast Cancer Study Group Trial 23-01 (Lancet Oncol. 2013;14:297-305) — found similar rates of regional recurrence in both groups. This suggests that "breast radiotherapy may be sufficient for most patients after a positive sentinel node biopsy," he noted. "That would spare many individuals from the arm edema and decreased arm mobility that axillary radiotherapy can cause."

Dr. Wallace agrees. "To me this affirms that you don't necessarily need to operate on the axilla. Now the question is, does the axilla really need treating at all?" she told Medscape Medical News.

"I think in the United States we've stopped doing lymph node dissection for sentinel-node-positive lumpectomy patients.... But the big question in all of our tumor boards is how much should we radiate."

She said the AMAROS protocol — radiation for 3 levels of the axilla — is "disappointing" because this approach would currently be considered overtreatment. "Normally, a patient with 1 positive lymph node undergoing lumpectomy would not get axillary radiation. We would irradiate the whole breast and get a little bit of the first level of the lymph nodes," she explained.

 
Radiation doctors who were on the fence about how much radiation to give are going to feel this shows good control. Dr. Anne Wallace
 

"Now we're going to be jumping into more radiation than someone would have gotten for 1 or 2 or 3 positive lymph nodes," Dr. Wallace continued. "I have really thoughtful radiation colleagues at UCSD; they call their colleagues, they comb the literature, they just don't take the attitude that they're going to irradiate everything. But now they're going to have these data that show somebody did irradiate everything and this was the recurrence rate. Now they may feel obligated to over-radiate. The radiation doctors who were on the fence about how much radiation to give are going to feel this shows good control," she said.

Although the trial showed lower rates of lymphedema with radiation than with surgery, a 5-year rate of 14% is still high, she said, and that rate will likely increase. "The fibrosis that you get with radiation continues over time, so at 5 years we may not see the complete lymphedema rate," she said. We see people 8 and 10 years after radiotherapy with rampant fibrosis that has developed over time."

Dr. Recht said that studies such as the Dutch MIRROR registry have identified subgroups that might benefit more from ALND than from axillary radiotherapy or breast radiotherapy (Ann Surg. 2012;255:116-121); however, the small number of regional nodal failures in the AMAROS and other trials make it very difficult to define such subgroups.

Although most patients in the AMAROS trial underwent lumpectomy, the small proportion who underwent mastectomy might be a group for whom ALND should still be considered, he added.

"The risk of local failure in patients treated with lumpectomy alone is high enough in most patient subgroups (20% to 30%) that giving radiation reduces the ultimate risk of distant relapse, as well as local failure," Dr. Recht explained.

"However, it's much harder for me to justify the potential side effects of radiation (which include rare secondary cancers) and the length of time it takes, compared with ALND, in patients who do not 'need' postmastectomy radiation to prevent a local recurrence. The risk of local failure after mastectomy varies much more, depending largely on the number of nodes involved. Most patients with 1 to 3 positive nodes have a risk of locoregional failure of less than 10% to 15%; at this level, there is only a minimal advantage, if any, for long-term cancer-specific survival from radiation. I have refused to treat patients who have had mastectomy if the only reason is to control disease in the axilla after sentinel node biopsy because of these considerations," he said.

Ultimately, although the AMAROS trial provides firm data about surgery, the open questions about radiation merit careful consideration, said Dr. Wallace.

"In the United States, we have women who are very reluctant to undergo radiation. They're worried about long-term side effects because there is progressive fibrosis and secondary malignancies with radiation. We have to make sure that we're not adding more radiation than we would have to their treatment," she noted.

The study authors, Dr. Wallace, and Dr. Recht have disclosed no relevant financial relationships.

2013 Annual Meeting of the American Society of Clinical Oncology: Abstract LBA 1001. Presented June 3, 2013.

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