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Intraoperative Radiotherapy for Breast Cancer: Its Perceived Simplicity

Intraoperative Radiotherapy for Breast Cancer: Its Perceived Simplicity

Over one-quarter of a million cases of breast cancer are diagnosed in the United States each year, many of which are early stage. The radiotherapeutic options after breast-conserving surgery in early-stage breast cancer are evolving quickly, with a focus on minimizing treatment volume, toxicity, and treatment duration. One such emerging option is intraoperative radiotherapy (IORT), administered either as a single fraction or as a boost. With many centers seeking to adopt such technology, there are licensing, proctoring, staffing, technical support, and reimbursement issues that need to be considered. We have reviewed the current international experience and describe one community cancer center’s experience with initiating an IORT breast cancer program.

Over 226,000 cases of breast cancer are diagnosed annually in the United States.[1] Local therapeutic strategies for early breast cancer have changed greatly over the past 3 decades. After multiple prospective randomized clinical trials demonstrated equivalent survival, the standard-of-care options have transitioned from radical surgery only (ie, total mastectomy) to a bimodality treatment consisting of breast-conserving surgery (BCS; partial mastectomy, segmentectomy, lumpectomy) followed by whole-breast irradiation (WBI).[2,3] Subsequently, a number of clinical trials evaluated the required role of radiotherapy in breast conservation. Survival was not compromised in the cohorts of patients in whom radiotherapy was omitted, but the local recurrence rates were found to be unacceptably high, thus securing the importance of radiation as a component of treatment.[4-7]

While WBI significantly reduces the risk of local recurrence, it is associated with significant costs. Conventional WBI ranges from 5 to 7 weeks of daily treatments, with the associated inconvenience and financial burden. Distance to a radiation center, the need to find transportation for the daily treatments, physical limitations, and/or lack of family support prevent many patients from selecting breast-conserving therapy. In addition, WBI is associated with potential acute and chronic toxicities to the surrounding normal tissue, such as dermatitis, soft-tissue fibrosis, rib fractures, hyperpigmentation, volume loss in the treated breast, and increased risk of cardiac disease in patients with left-sided breast cancer.[8]

An attractive therapeutic alternative to WBI would be a treatment that has at least equivalent efficacy while reducing overall toxicity and treatment duration. The concept of partial or accelerated partial-breast irradiation (APBI) was introduced to address several of the drawbacks of WBI. Intraoperative radiotherapy (IORT) is a form of partial-breast radiotherapy that delivers radiation to the tumor bed. This treatment can reduce or even eliminate the need for WBI. Such a treatment strategy has the potential to significantly reduce normal tissue toxicity. IORT avoids radiation to the skin and limits radiation to the surrounding normal breast tissue since it is a form of partial-breast irradiation. Radiation dose to the deeper structures, such as the heart, lung, and ribs, is greatly reduced, since IORT utilizes an electron or low-energy x-ray. In addition, a shielding device is often employed over the chest wall to further reduce the radiation dose to the deeper, normal tissues. Direct visualization of the target volume at the time of treatment also ensures appropriate coverage of the breast tissue at risk.

TABLE 1

Single-Fraction and Boost IORT Studies for Breast Cancer

Over the past decade, the use of IORT in breast cancer has steadily increased. It is increasingly being used as a replacement for the electron boost portion of breast radiation, or in appropriately selected patients as the replacement for the entire course of WBI. The first clinical data on IORT boost were reported by Lemanski et al.[9] The 50 early-stage breast cancer patients in their initial series were treated with 10 Gy IORT followed by 50 Gy WBI (Table 1). These patients had excellent cosmesis and a low toxicity profile; two patients had a local recurrence. Soon after, a group from Salzburg[10] reported their results in 378 stage I and II breast cancer patients who received BCS and postoperative radiation therapy (50−54 Gy), but different boost strategies. A total of 188 were treated with standard electron boost (12 Gy), and the other 190 patients were treated with IORT boost radiation (9 Gy). Their data showed 5-year actuarial rates of ipsilateral breast tumor recurrence (IBTR) of 4.3% and 0.0% in the standard electron boost and IORT boost groups, respectively. They concluded that IORT boost yielded a statistically significant decrease in the rate of IBTR compared with a similar cohort treated with standard electron boost. A pooled European analysis of 1,110 patients treated with IORT boost also reported encouraging results regarding this treatment strategy. With a median follow-up of over 73 months, the analysis identified only 16 patients with IBTR, yielding a 99.2% local control rate. At 7 years, 88% disease-free survival, 93% disease-specific survival, and 90% overall survival were reported.[11] Our results at St. Joseph Hospital (Orange, Calif) have confirmed excellent tolerance of IORT boost accompanying WBI. None of the 50 patients treated at our center experienced grade 3 or greater toxicity. Two patients had delayed wound healing, but there were no wound infections.[12] Longer follow-up will be needed before we can confirm tumor control rates.

The role of IORT boost has also been explored in combination with hypofractionated WBI. A series from Milan was published that reviewed 211 women with a diagnosis of early-stage breast cancer treated with BCS. These patients were treated with a 12-Gy IORT boost followed by 37.05 Gy WBI in 13 daily fractions of 2.85 Gy. Of the 108 patients who were evaluated for late toxicity, one patient had grade 3 and one had grade 4 skin toxicity. The remaining 106 patients had grade 2 or lower skin toxicity. Given that the median follow-up in this series was 9 months, longer follow-up is required to determine treatment efficacy.[13] In our own institutional study, we have seen similar excellent tolerance of IORT boost with hypofractionated WBI. Data regarding tolerance and efficacy will continue to emerge as other studies continue to enroll patients for evaluation of this treatment combination. 

More recently, there has been great interest in using IORT to replace the entire course of WBI. The approach of employing IORT as a “single-fraction” treatment was first used at the European Institute of Oncology (EIO) in Milan, Italy, in 1999. The EIO eventually progressed to a phase III study, which started in 2002 and finished accruing patients in 2009. Results from this trial are currently pending. However, the EIO researchers have published results on 1,822 patients who were treated “off protocol” with IORT.[14] These patients were treated with a single 21-Gy fraction between 2000 and 2008, with a median follow-up of 36 months. A 2.3% local recurrence rate was reported, with 5-year and 10-year survivals of 97% and 90%, respectively. Local side effects were primarily fat necrosis (4.2%) and fibrosis (1.8%). A smaller phase II French trial reported on 94 patients also treated with a single
21-Gy fraction.[15] The median follow-up in this trial was 30 months, and the median age was 72 years. No acute grade 3 toxicity was observed. Only two patients experienced recurrence, and cosmesis was reported to be good to excellent. While results of the EIO randomized trial are pending, single-institution and early-phase studies have indicated that single-fraction IORT is safe and effective in appropriately selected patients. The results of these studies are summarized in Table 1.

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