Elsevier

The Lancet Oncology

Volume 14, Issue 13, December 2013, Pages 1269-1277
The Lancet Oncology

Articles
Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial

https://doi.org/10.1016/S1470-2045(13)70497-2Get rights and content

Summary

Background

Intraoperative radiotherapy with electrons allows the substitution of conventional postoperative whole breast irradiation with one session of radiotherapy with the same equivalent dose during surgery. However, its ability to control for recurrence of local disease required confirmation in a randomised controlled trial.

Methods

This study was done at the European Institute of Oncology (Milan, Italy). Women aged 48–75 years with early breast cancer, a maximum tumour diameter of up to 2·5 cm, and suitable for breast-conserving surgery were randomly assigned in a 1:1 ratio (using a random permuted block design, stratified for clinical tumour size [<1·0 cm vs 1·0–1·4 cm vs ≥1·5 cm]) to receive either whole-breast external radiotherapy or intraoperative radiotherapy with electrons. Study coordinators, clinicians, and patients were aware of the assignment. Patients in the intraoperative radiotherapy group received one dose of 21 Gy to the tumour bed during surgery. Those in the external radiotherapy group received 50 Gy in 25 fractions of 2 Gy, followed by a boost of 10 Gy in five fractions. This was an equivalence trial; the prespecified equivalence margin was local recurrence of 7·5% in the intraoperative radiotherapy group. The primary endpoint was occurrence of ipsilateral breast tumour recurrences (IBTR); overall survival was a secondary outcome. The main analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01849133.

Findings

1305 patients were randomised (654 to external radiotherapy and 651 to intraoperative radiotherapy) between Nov 20, 2000, and Dec 27, 2007. After a medium follow-up of 5·8 years (IQR 4·1–7·7), 35 patients in the intraoperative radiotherapy group and four patients in the external radiotherapy group had had an IBTR (p<0·0001). The 5-year event rate for IBRT was 4·4% (95% CI 2·7–6·1) in the intraoperative radiotherapy group and 0·4% (0·0–1·0) in the external radiotherapy group (hazard ratio 9·3 [95% CI 3·3–26·3]). During the same period, 34 women allocated to intraoperative radiotherapy and 31 to external radiotherapy died (p=0·59). 5-year overall survival was 96·8% (95% CI 95·3–98·3) in the intraoperative radiotherapy group and 96·9% (95·5–98·3) in the external radiotherapy group. In patients with data available (n=464 for intraoperative radiotherapy; n=412 for external radiotherapy) we noted significantly fewer skin side-effects in women in the intraoperative radiotherapy group than in those in the external radiotherapy group (p=0·0002).

Interpretation

Although the rate of IBTR in the intraoperative radiotherapy group was within the prespecified equivalence margin, the rate was significantly greater than with external radiotherapy, and overall survival did not differ between groups. Improved selection of patients could reduce the rate of IBTR with intraoperative radiotherapy with electrons.

Funding

Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, and Umberto Veronesi Foundation.

Introduction

Until the 1970s, surgical management of breast cancer was based on the Halsted mastectomy, with minor modifications. From the 1970s, studies1, 2, 3 showed that breast-conserving surgery plus radiotherapy resulted in much the same outcomes as the Halsted mastectomy for tumours up to 5 cm in size; however, when radiotherapy was omitted, women had an increased likelihood of local recurrence.4, 5 Thus, breast-conserving surgery followed by whole breast irradiation became the mainstay of surgical treatment for small breast carcinoma. In the past 10 years, new regimens have been developed: studies6 have shown that the duration of whole breast irradiation can be abbreviated from 6 weeks to 3 weeks and partial breast irradiation has reduced the irradiation field to the quadrant in which the carcinoma arose.7

Despite these advances, most women are still required to attend postoperative radiotherapy for about 30 days consecutively. Many women living a substantial distance from a radiotherapy centre have serious difficulties attending every day, especially those living in small villages, mountainous regions, or islands. Intraoperative radiotherapy, in which postoperative whole breast irradiation is substituted for one session of radiotherapy with the same equivalent dose during surgery, solves this problem.8 In this context, the European Institute of Oncology developed electron intraoperative radiotherapy (ELIOT), which involves administering electrons in one session during surgery with a total dose of 21 Gy. Importantly, in most cases when a local recurrence occurs after conservative treatment a mastectomy is indicated. Nowadays, total mastectomy is generally skin-sparing and often nipple-sparing, with a prosthesis implant; the integrity of the skin is important for the success of the operation. Previously irradiated skin can undergo necrosis, whereas skin damage is largely avoided with intraoperative radiotherapy with electrons. However, the expected advantages in quality of life must be balanced with any possible increase in recurrence.

The European Institute of Oncology began treating patients with intraoperative radiotherapy with electrons in 1999, and the outcomes of patients treated outside of clinical trials have been reported.9 We present the results of a randomised equivalence study comparing local recurrence and overall survival after electron intraoperative radiotherapy with postoperative external radiotherapy.

Section snippets

Study design and patients

This single-centre study was done at the European Institute of Oncology (Milan, Italy), a comprehensive cancer centre and referral centre for the treatment of patients with breast cancer. Eligible patients were women aged 48–75 years with early breast cancer with a maximum tumour diameter up to 2·5 cm and suitable for breast-conserving therapy. The study protocol was approved by the institutional ethics committee and written informed consent was obtained from patients before assignment to

Results

1305 patients were randomised (654 to external radiotherapy and 651 to intraoperative radiotherapy) between Nov 20, 2000, and Dec 27, 2007 (figure 1). The outcomes were assessed 5 years from the end of the accrual (median follow-up for all patients 5·8 years [IQR 4·1–7·7]; for external radiotherapy 5·9 years [4·2–7·8]; for intraoperative radiotherapy with electrons 5·5 years [4·0–7·4]). The main analysis was by intention to treat. We also did a per-protocol analysis, excluding women allocated

Discussion

In women with early small breast carcinoma, intraoperative radiotherapy with electrons resulted in significantly higher local recurrence than did conventional postoperative external radiotherapy after 5 years of follow-up. Both true local recurrences (in the index quadrant) and new ipsilateral breast tumours were significantly more common in the intraoperative radiotherapy group than in the external radiotherapy group. Overall survival did not differ between the groups, with about the same

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