Two Studies: Internal Mammary RT Ups Breast Cancer Survival

Kate Johnson

April 09, 2014

VIENNA — Irradiation of the internal mammary lymph nodes, even in patients with left-sided breast cancer, improves outcomes without significantly increasing cardiac or lung toxicity, according to 2 large studies, each with about 10 years of follow-up. Both were presented here at the European Society for Radiotherapy and Oncology 33.

"Given the evidence from this and other studies, the benefits of regional nodal irradiation can no longer be dismissed, and must be discussed with the majority of high-risk patients," said Bruce Haffty, MD, professor in the Department of Radiation Oncology at Rutgers Robert Wood Johnson Medical School and associate director of the Cancer Institute of New Jersey in New Brunswick. He acted as discussant for both studies.

"Given the breast cancer mortality benefit, the distant metastasis benefit, and the overall survival benefit, it is imperative that we at least discuss the pros and cons of regional nodal irradiation in these patients, whether treated with breast-conserving surgery or mastectomy," Dr. Haffty told delegates at the meeting.

The findings come from 2 large and quite different studies; one conducted in several European countries and the other conducted in Denmark.

The European study, known as the Internal Mammary Irradiation Trial, was conducted by the EORTC Radiation Oncology Group and Breast Cancer Group.

The researchers randomized more than 4000 patients to internal mammary and medial supraclavicular (IM-MS) irradiation or to no irradiation, and followed them for more than 10 years to assess overall survival, disease-free survival, and metastasis-free survival.

The Internal Mammary Node study, conducted by the Danish Breast Cancer Cooperative Group (DBCG), was not randomized, but had similar end points and duration of follow-up. It compared patients with right-sided breast cancer who received IM-MS irradiation with patients with left-sided disease did not. The DBCG stopped using IM-MS irradiation for patients with left-sided breast cancer in 2003 because of cardiac risk.

Both studies found a survival benefit in patients whose internal mammary nodes were irradiated, with no significant increase in cardiac or lung toxicity.

"With today's very advanced treatment techniques making it possible to adapt the delivery of radiotherapy to the anatomy of each individual patient, it is becoming increasingly difficult to find good arguments against regional radiotherapy," said DBCG investigator Lise Thorsen, MD, from Aarhus University Hospital in Denmark.

Radiotherapy to the internal mammary nodes "should be considered in patients with positive axillary nodes," especially if many nodes are positive or there is a large medial tumor, she told Medscape Medical News.

There was consensus on this point. "We advise to strongly consider radiation therapy to the internal mammary and supraclavicular lymph nodes for patients with involved axillary lymph nodes and/or a medially located primary tumor," said EORTC investigator Philip Poortmans, MD, from Institute Verbeeten in Tilburg, the Netherlands.

When he reported preliminary findings at the European Cancer Congress last year, Dr. Poortmans said that a debate has been raging for some 20 years over whether or not to irradiate internal mammary lymph nodes.

He told Medscape Medical News that, currently, "a shift toward more regional radiotherapy is taking place in Europe," but he added that "more reluctance can be felt in the United States."

In fact, in the United States, there is a wide range in practice concerning internal lymph node irradiation, with no consensus, said Thomas Buchholz, MD, professor in the Department of Radiation Oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

"At our institution, we advocate that, for appropriately selected breast cancer patients, the internal mammary nodes at risk — those within the first 3 interspaces, most of which are above the heart — should be included in the radiation fields, and conformal techniques should be used to minimize the dose to the heart," Dr. Buchholz told Medscape Medical News.

Even with the 2 new studies, which involved more than 7000 patients, the benefits of internal mammary irradiation barely reached statistical significance, Dr. Thorsen noted. However, the risks might not have had enough time to fully emerge. "We must be aware that some of the possible late side effects appear more than a decade after initial treatment, making long-term follow-up a necessity," she cautioned.

European Study Results

The EORTC study involved 4004 patients from 46 centers in 13 countries. The median age of the cohort was 54 years, 59% of the patients were postmenopausal, and axillary lymph nodes were affected in 55.6% of the patients. Of the cohort, 33.8% had stage I disease, 52% had stage II disease, and 14.2% had stage III disease.

The 2002 patients randomized to irradiation of the IM-MS received up to 50 Gy delivered in 25 fractions; the other 2002 patients were randomized to no irradiation of the IM-MS.

Of the 76.1% of patients treated with breast-conserving surgery, 85.0% received a radiation boost to the primary tumor bed.

For patients who underwent mastectomy, 73.2% received chest wall irradiation; axillary irradiation was received by 6.8% of the no IM-MS group and by 7.8% of the IM-MS group.

Axillary dissection was total in 54.0% of all patients and partial in 38.0%, and 7.1% of patients underwent a sentinel node procedure; there were no differences between groups for these rates.

Adjuvant systemic treatment, given to 99.0% of node-positive and 66.3% of node-negative patients, consisted of chemotherapy plus hormone therapy in about one third of patients, chemotherapy in about one third, and hormone therapy in about one third.

The primary end point was overall survival; secondary end points were disease-free survival, metastasis-free survival, and cause of death.

After a median follow-up of 10.9 years, there were more breast cancer deaths in the no IM-MS group than in the IM-MS group (21.4% vs 19.1%; hazard ratio [HR], 0.87).

The rate of other causes of death, including other cancers and cardiovascular causes, was similar in the 2 groups.

This led to a nonsignificant benefit in overall survival at 10 years of 80.7% in the no IM-MS group and 82.3% in the IM-MS group (HR, 0.87; 95% confidence interval, 0.76 - 1.00; = .0556).

"After adjustment for stratification factors, this became statistically significant (= 0.0496), and the number needed to treat is 39," Dr. Poortmans reported.

Pathologic N-stage did not affect outcome, but there was a clear influence of treatment, depending on the number of nodes removed. The result was better in patients who had fewer than 10 nodes removed, compared with more than 10. "Here, the number needed to treat for overall survival is only 13," he said.

There was a nonsignificant trend in favor of chemotherapy plus hormonal therapy over either therapy alone, with a number needed to treat of 20.

For the disease status end points of regional lymph node recurrence, distant metastases, and second breast cancers, "there was not much of a difference between groups. The big difference was in distant recurrence," said Dr. Poortmans, with fewer distant metastases in the IM-MS group (15.9% vs 19.6%).

Disease-free survival was better in the IM-MS group than in the no IM-MS group (72.1% vs 69.1%; HR, 0.89; P = .044), with a number needed to treat of 30. Metastasis-free survival was also better in the IM-MS group (78.0% vs 75.0%; HR, 0.86; P = .020), with a number needed to treat of 29.

There was a slightly higher rate of toxic effects in the IM-MS group, but the rates were low and the difference between groups was not statistically significant, he stressed.

Toxic effects included cardiac fibrosis (1.3% vs 0.7%, P = .07) and any evidence of cardiac disease (8% vs 6.9%; P = .20), although for patients with left-sided breast cancer, the outcome was not significantly worse. There was a significantly increased rate of lung toxicity in IM-MS group (6.8% vs 3.0%; P < .0001).

Danish Study: Stricter End Points

In the DBCG trial, prognostic factors were no different between the 1485 patients with right-sided disease who received irradiation and the 1585 with left-sided disease who did not. All patients were node-positive, which is a major difference from the EORTC trial, Dr. Thorsen noted.

Additionally, the type of surgical and systemic treatment was similar in the 2 groups, she said.

After a median follow-up of 9 years, the primary end point of overall survival was higher in the irradiated group than in the nonirradiated group (72.2% vs 67.8%; HR, 0.84; P = .03).

The secondary end point of metastatic disease was lower in the irradiated group, but the difference was not significant (26.9% vs 28.7%; HR, 0.90). Breast cancer death was lower, but barely reached significance (23.5% vs 25.5%; HR 0.85; P = .04).

The end points in this trial were "more strict" than those in the EORTC study, said Dr. Thorsen.

"Patients in the DBCG study who develop metastatic disease after another type of event (isolated local, regional, opposite-breast, or other malignant disease) do not count in the calculated cumulated incidence of metastatic disease," she explained. "This makes for a very conservative estimate, and causes a loss of power to detect a difference."

A subgroup analysis of the DBCG data showed that the benefit of irradiation increased with increasing tumor size, increasing number of lymph nodes involved, and a medial or central tumor localization, Dr. Thorsen noted.

Dr. Thorsen, Dr. Poortmans, and Dr. Buchholz have disclosed no relevant financial relationships.

European Society for Radiotherapy and Oncology (ESTRO) 33: Abstracts OC-0148 and OC-0523. Presented April 5, 2014.

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