Targeted Intraoperative Radiotherapy for Breast Cancer in Patients in Whom External Beam Radiation Is Not Possible

Purpose

External beam radiation therapy (EBRT) following wide local excision of the primary tumor is the standard treatment in early breast cancer. In some circumstances this procedure is not possible or is contraindicated or difficult. The purpose of this study was to determine the safety and efficacy of targeted intraoperative radiotherapy (TARGIT) when EBRT is not feasible.

Methods and Materials

We report our experience with TARGIT in three centers (Australia, Germany, and the United Kingdom) between 1999 and 2008. Patients at these centers received a single radiation dose of 20 Gy to the breast tissue in contact with the applicator (or 6 Gy at 1-cm distance), as they could not be given EBRT and were keen to avoid mastectomy.

Results

Eighty patients were treated with TARGIT. Reasons for using TARGIT were 21 patients had previously received EBRT, and 31 patients had clinical reasons such as systemic lupus erythematosus, motor neuron disease, Parkinson's disease, ankylosing spondylitis, morbid obesity, and cardiovascular or severe respiratory disease. Three of these patients received percutaneous radiotherapy without surgery; 28 patients were included for compelling personal reasons, usually on compassionate grounds. After a median follow-up of 38 months, only two local recurrences were observed, an annual local recurrence rate of 0.75% (95% confidence interval, 0.09%–2.70%).

Conclusions

While we await the results of the randomized trial (over 2,000 patients have already been recruited), TARGIT is an acceptable option but only in highly selected cases that cannot be recruited in the trial and in whom EBRT is not feasible/possible.

Introduction

Wide local excision of the primary tumor, followed by postoperative external beam radiotherapy (EBRT) to the whole breast is now considered the standard management for most patients with early breast cancer. This approach ensures that the majority of patients will enjoy long-term local control of the disease with an acceptable cosmetic result 1, 2, 3, 4. There are a number of circumstances in which treatment by this standard method proves difficult, either because of previous radiation (for example, in the case of patients with recurrent cancer in the same breast or those who have been treated with “mantle” radiotherapy for Hodgkin's disease) or because of comorbidities such as severe respiratory problems, collagen or autoimmune disorders, chronic lung disease with respiratory dysfunction, or painful arthritis (which might prevent adequate abduction of the shoulder). Extreme age and geographical considerations may also be confounding factors in the delivery of EBRT, bearing in mind the traveling required, generally on a daily basis for at least 3 weeks or more to the radiation oncology center.

This paper reports the experience of three major centers in the United Kingdom, Australia, and Germany, all of which have extensive experience in administering intraoperative radiation therapy (IORT) for patients with early breast cancer. These centers along with 22 others are participating in an international randomized trial targeted intraoperative radiotherapy (TARGIT), comparing EBRT with IORT alone, which was launched in March 2000 and has now accrued over 2,000 patients 5, 6, 7, 8, 9. In each of these three centers, patients have been seen for consideration of inclusion within this randomized trial. In selected cases of patients who failed to meet the inclusion criteria and after careful consideration at the respective multidisciplinary meetings, IORT was offered outside the randomized trial, following wide local excision surgery as an alternative to EBRT (Table 1). In addition, a small group of patients with estrogen receptor-negative tumors who were considered unfit even for wide local excision or who refused surgery have been treated by “percutaneous” IORT alone without any surgical intervention.

There is little in the published literature to help with difficult judgments regarding the appropriateness of EBRT in patients with significant comorbidity. For example, some radiation oncologists are reluctant to offer EBRT to patients with systemic lupus erythematosus (SLE), as the oncologists are concerned about significant risk of excess radiation damage to which can be long-lasting 10, 11, 12. Likewise, in the case of patients with respiratory dysfunction, the radiation oncologist might well be more concerned with the inevitable “splash” of the radiation field to the outer portion of ipsilateral lung than would normally be the case. In patients previously treated with radiotherapy, such as those with Hodgkin's disease treated and cured by mantle irradiation, most oncologists would be unwilling to agree to conventional dose EBRT, even with a gap of 20 years or more between the initial radiation and the second course.

Recently, we have discovered a novel mechanism of action of radiotherapy (13). We found that wound fluid collected over the first 24 hours immediately after lumpectomy stimulates the proliferation, motility, and invasiveness of breast cancer cells. All these stimulatory effects of normal wound fluid were abrogated if the patient had received targeted intraoperative radiotherapy. Thus, this action of TARGIT creates a microenvironment that is not conducive to tumor growth, and this novel mechanism could act synergistically with its tumoricidal effect.

In this paper, we describe 80 patients who were not suitable for the TARGIT randomized trial by virtue of their inability to accept the EBRT arm of the trial but nonetheless had compelling indications for breast-conserving surgery, and refusal to accept mastectomy as an option, we felt that TARGIT was at least better than no radiotherapy at all. We have compiled this brief report to point out to colleagues that even in these difficult circumstances, where EBRT is felt to be impossible or ill-advised, it may still be possible to avoid mastectomy by offering wide local excision surgery followed by IORT. The median follow-up of these patients was 38 months.

This paper focuses mainly on the efficacy of the treatment in a selected, albeit heterogeneous, group of patients, as the safety of using IORT has already been reported widely 14, 15, 16, 17.