Kate Johnson

April 22, 2013

Geneva, Switzerland — Five-year results of the Electron Intra Operative Radiation Therapy (ELIOT) trial carry a strong message about the importance of selection of patients with breast cancer, according to Roberto Orecchia, MD, from the Department of Radiation Oncology at the European Institute of Oncology in Milan, Italy.

As the current era of smaller tumor identification spurs interest in partial- rather than whole-breast irradiation, intraoperative radiation therapy offers a skin-sparing advantage over other forms of partial-breast radiation therapy, he said here at the 2nd European Society for Radiotherapy & Oncology (ESTRO) Forum.

However, the 5-year data from the ELIOT trial show a surprising discrepancy in local recurrence rates in favor of postoperative whole-breast irradiation. "The main issue for the future is to increase our capability to select patients," Dr. Orecchia said, noting that certain subgroups of ELIOT-treated patients had more acceptable local relapse rates than others.

So far, survival has not differed between the patients who underwent partial-breast irradiation and those who had whole-breast irradiation.

"At this moment, in my mind partial-breast irradiation should not be offered yet outside of a trial," commented John Yarnold, MD, professor of clinical oncology at the Royal Marsden Cancer Hospital in London, United Kingdom, who acted as discussant of the session in which the results were presented.

"Randomized trials, particularly in partial-breast radiotherapy where we're really evaluating the other quadrant of the breast, take time to mature — and we really have to wait 5 to 10 years," Dr. Yarnold told Medscape Medical News.

It may turn out that partial-breast irradiation is suitable for only a small subgroup of patients, who "could represent really quite a small population of our patients," he commented. However, "ultimately the arbiter is the patient. There will be women, particularly depending on where they are in the world who will actually opt for this treatment, maybe as an alternative to losing their breast, particularly if they don't have access to standard radiotherapy."

Latest Results From ELIOT

ELIOT, a single-institution trial that ran from November 2000 to December 2007, included patients with breast cancer, aged 48 years or older, with a tumor size no larger than 2.5 cm. After undergoing standard breast-conserving surgery, they were randomly assigned to receive an intraoperative single-fraction ELIOT treatment of 21 Gy to the tumor bed (n = 651) or conventional radiation therapy consisting of a 50-Gy postoperative external-beam dose to the whole breast with conventional fractionation plus a 10-Gy boost (n = 654).

The 5-year results now presented in Geneva were based on data available for 601 conventionally treated and 585 ELIOT-treated patients. They show a significant difference in the local recurrence rates, with "a very low" local recurrence rate of 0.7% seen in the conventional group compared with 5.3% in the ELIOT group (P = .0002), Dr. Orecchia reported.

An analysis of the types of failures showed that the number of true local relapses was significantly higher in the ELIOT group (20 vs 4; P = .0004).

"New" breast cancer, defined as occurring in another quadrant of the same breast, accounted for some of this (21 cases in the ELIOT group vs 12 in the conventionally treated group; P = .06), but most of the difference was in "ipsilateral cancer" (14 vs 0 cases; P < .0001).

Cancers in the contralateral breast occurred less frequently in the ELIOT group, although the difference was not statistically significant (7 cases vs 12; P = .35).

No Difference in Survival

The good news for ELIOT-treated patients is that this significantly higher rate of local relapse "has not been translated to survival," Dr. Orecchia commented. "We have exactly the same number of deaths in both arms and no statistical difference with respect to overall survival in the conventional versus ELIOT arms. This similarity stretches beyond the 5-year analysis into 6, 8, and 10 years of follow-up (95.3% vs 94.6%, 93.5% vs 92.1%, and 92% vs 89.8%; P = .69).

However, despite the skin-sparing attractiveness of intraoperative radiation therapy, ELIOT-treated patients still had their share of toxicities.

The overall toxicity favored the ELIOT group (P = .0002), especially because of the low incidence of skin erythema (P < .0001), dry skin (P = .04), hyperpigmentation (P = .0004), breast edema (P = .004), and breast itching (P = .002). However, there was greater toxicity in the ELIOT group than in the conventional radiation group in terms of fat tissue necrosis, both from the clinical point of view (12% incidence) and by imaging (incidence, 16%; P = .04 for both), Dr. Orecchia said.

The incidence of skin atrophy, retraction, pain, and burning did not differ between the groups.

In addition, "an important point, and one of the most controversial issues in applying such a high single dose, is the possibly higher incidence of subcutaneous fibrosis at the tumor bed in the ELIOT arm — which we did not observe," Dr. Orecchia commented.

Pulmonary fibrosis was found in 23.6% of a subgroup of patients who agreed to this assessment by computed tomography, with 90% of these occurring in the conventional group and 10% (n = 4) in the ELIOT group (P < .0001).

Most of the cases of pulmonary fibrosis were grade 1 (n = 26, of which only 1 case was in the ELIOT group) or grade 2 (n = 15, of which 3 were in the ELIOT group). Only 1 patient developed grade 3 fibrosis.

On the basis of this subgroup analysis, the post–radiation therapy risk of developing grade 1 pulmonary fibrosis was 19 times higher for conventionally treated patients than for ELIOT patients (odds ratio, 19.20), and the risk for grade 2 pulmonary fibrosis was 6 times higher (odds ratio, 5.7).

Future Focus on Subgroups

Dr. Orecchia concluded that the results show a clear distinction between subgroups of patients, which should be the main focus with ELIOT in the future. "We observed in our trial that we have an acceptable, lower local relapse rate using ELIOT in some subgroups of patients," he said, "particularly in women with small (1 to 1.5 cm), well-differentiated tumors, with a low proliferation index (Ki-67 < 20%), luminal A tumors," as well as women who are stratified as suitable for APBI [accelerated partial-breast irradiation] according to ASTRO [American Society of Radiation Oncology] guidelines."

"Based on these results we now propose subsequent whole-breast irradiation in certain patients after ELIOT," he added, specifying that these patients include those with tumors larger than 2.0 cm, as well as those with 4 or more positive nodes, high-grade tumors, or triple-negative tumors.

Proceed With Caution

Reached by Medscape Medical News to comment on the findings, Frank Vicini, MD, who recently cowrote a commentary on intraoperative therapy titled "On the Road to Intraoperative Radiotherapy: More 'Proceed With Caution' Signs" (Oncology (Williston Park). 2013;27:113-114, 122) said, "It is important to determine whether or not the ELIOT trial results are technique-specific or apply to other types of intraoperative radiation."

"Clearly, there are 3 concepts that need to be addressed," continued Dr. Vicini, from William Beaumont Hospital in Royal Oak, Michigan.

"Is the delivered dose adequate? Was the dose delivered accurately and optimally? And are the higher local recurrence rates secondary to the fact that these patients did not receive whole-breast irradiation or simply to a suboptimal technique/concept? Only further analyses and results from other trials of intraoperative radiation therapy can help clarify these issues," he said.

It is being studied and used at only a small group of centers. Dr. Frank Vicini

Dr. Vicini said results from both the ELIOT and the Targeted Intraoperative Radiotherapy (TARGIT) (previously reported by Medscape Medical News) trials have resulted in "some support" for intraoperative radiation therapy in the United States.

"However, neither technique has gained a large following in the US yet. It is being studied and used at only a small group of centers," he continued. "Many groups have noticed the less than optimal results of both trials, and some concern has been justifiably raised as to the efficacy of these techniques."

In his commentary, Dr. Vicini and colleagues write, "the ELIOT experience as reported in the interim results of the randomized trial have produced not one but two major reasons for pessimism — suboptimal tumor control and higher toxicity….The ELIOT results amply highlight the perils of poor patient selection that may come with [intraoperative radiation therapy]."

None of the speakers have disclosed any relevant financial relationships.

2nd European Society for Radiotherapy & Oncology (ESTRO) Forum. Abstract OC-0234. Presented April 21, 2013.


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