Strut-Adjusted Volume Implant: A Targeted Radiation Treatment in Breast Cancer

Keywords:

• accelerated partial breast irradiation
• brachytherapy
• breast carcinoma
• strut-adjusted volume implant
• TARGIT

The standard of care for breast conservation has been a lumpectomy followed by whole breast irradiation (WBI) [1,2]. However, emerging evidence argues that in appropriately selected candidates, irradiation of only the most at-risk portion of the breast may be adequate. Partial breast irradiation (PBI) takes 1–5 days, depending on the method, and may replace the traditional 6 weeks of WBI in some women. These shorter courses of irradiation spare normal tissues such as adjacent ribs, lung and heart. Multiple methods of PBI exist and are described in the literature, each with unique strengths and weaknesses. This article describes one of the newer devices, the strut-adjusted volume implant (SAVI^®; Cianna Medical, CA, USA) used over a 5-day course, and compares it with an intraoperative method, INTRABEAM^® (Zeiss AG, Germany) used at the time of lumpectomy.

Partial breast irradiation is predicated on historical data demonstrating that the area of the breast most likely to suffer a recurrence is adjacent to the original tumor [3]. In fact, ‘elsewhere’ breast tissue is not only at lower risk, but the data do not demonstrate decreased ‘elsewhere’ recurrences with WBI. In addition, emerging clinical data support the efficacy and safety of PBI. Several retrospective studies reveal excellent local control, and there are three prospective, randomized studies comparing PBI with WBI reporting equivalent local control and better cosmesis with PBI [4–6]. One of these trials compared intraoperative therapy using the INTRABEAM device with WBI (Targeted Intraoperative Radiotherapy [TARGIT] trial), and reported similar local control with less grade 3–4 toxicity with the intraoperative therapy at 4 years [5].

More data comparing PBI and WBI are expected in the near future. There is an open, prospective, randomized trial in North America sponsored by the National Cancer Institute (NCI), the National Surgical Adjuvant Breast and Bowel Project (NSABP-39) and the Radiation Therapy Oncology Group (0413) that has randomized eligible patients between WBI and accelerated PBI (APBI) using one of three methods: interstitial brachytherapy, 3D conformal radiotherapy or balloon brachytherapy. In addition, there are at least three other randomized prospective trials evaluating APBI ongoing worldwide: the Groupe Européen de Curiethérapie – European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) trial, the Canadian Ontario Clinical Oncology Group Randomized Trial of Accelerated Partial Breast Irradiation (RAPID) trial and the UK Intensity Modulated Partial Organ Radiotherapy Low-Risk (IMPORT LOW) trial.

The SAVI breast brachytherapy device is a multicatheter breast brachytherapy applicator that is inserted postoperatively and delivers highly conformal radiation treatment to the tissue adjacent to the lumpectomy cavity. The radiation dose is delivered twice daily for 1 week. The device consists of a central catheter surrounded by multiple peripheral catheters that, after insertion, expand to fit the lumpectomy cavity. It comes in four sizes to fit a variety of lumpectomy cavity volumes, each with a number of peripheral catheters to ensure maximal dose modulation. The flexible nature of the device minimizes patient discomfort, as the device remains in the breast over the course of treatment. As the radiation source is inserted only twice daily for approximately 10 min, the patient is not radioactive between treatments. The unique SAVI design allows maximal dosing flexibility, with the ease of a single-entry device. Each catheter is differentially loaded in order to provide highly conformal dose delivery optimized to the target tissue, while simultaneously minimizing dose to normal tissue such as the skin, chest wall, lung and heart. The central catheter’s most distal loading site extends beyond the distal loading site for each of the peripheral catheters, allowing projection of dose beyond the tip of the device, a feature unique among the single-entry devices.

Strut-adjusted volume implantation has increased the ability for small breasted women and those with tumor beds close to the skin or chest wall to receive APBI without the need for interstitial therapy, which is not commonly available in the USA. In one study, the device increased patient eligibility by as much as 40%, with excellent dosimetry, cosmesis and outcome, although results are still preliminary, with the first 102 patients reported at 21-month median follow-up [7,8]. The dosimetry is outstanding, with guidelines bridging those established by interstitial and MammoSite^® (Hologic, MA, USA) brachytherapy [9]. There are no randomized prospective data on any of the single entry devices comparing them with interstitial therapy or WBI, although there are 5-year nonrandomized data on the MammoSite device, demonstrating excellent control [10,11]. The SAVI device, similarly to the MammoSite, delivers 34 Gy to the target tissue adjacent to the original tumor.

Recently, a prospective, randomized, noninferiority trial comparing PBI using the INTRABEAM device (TARGIT trial) with WBI was reported [5]. The INTRABEAM device irradiates the tissue adjacent to the tumor bed in a single fraction at the time of lumpectomy [12]. INTRABEAM consists of a spherical tumor bed applicator (with varying sizes) at the end of a 3.2-mm diameter tube that emits low-energy x-rays (≤50 kV). Because of the low energy, room shielding is not required. After lumpectomy, the device is positioned within the surgical cavity with the at-risk tissue approximated to the applicator, and the tissue is irradiated over approximately 30 min. Although varying doses of radiation may be delivered, the dose used in this trial was 20 Gy at the surface of the tumor bed (delivering 5–7 Gy at 1 cm depth) [5]. After irradiation, the INTRABEAM device is removed and the surgical cavity closed.

The TARGIT trial, which began in March of 2000, took place at 28 centers in nine countries, enrolling 2232 women aged 45 years or more with invasive ductal carcinoma. Women were randomized to either PBI with the INTRABEAM or WBI (40–56 Gy ± 10–16 Gy boost). Reportedly, 14% of patients in the PBI arm ultimately received WBI owing to concerning findings on subsequent tissue pathologic examination. Median follow-up was not reported and less than 20% of patients had follow-up beyond 4 years. The estimated 4-year local recurrence was reported to be 1.20% in the INTRABEAM arm and 0.95% in the WBI arm (p = 0.41). The frequency of complications and major toxicity was similar; however, lower Radiation Therapy Oncology Group (RTOG) grade 3–4 toxicity (0.5 vs 2.1%) and a higher rate of wound seromas requiring three or more aspirations (2.1 vs 0.8%) were reported in the INTRABEAM arm.

Although both methods deliver PBI, the SAVI and INTRABEAM differ in many respects. INTRABEAM allows for completion of irradiation intraoperatively, whereas SAVI irradiation is delivered over 1 week. Because it is used intraoperatively, the INTRABEAM device does not allow for complete pathologic examination prior to irradiation; hence, some patients will still require WBI. Surgeon and radiation oncologist schedules must be coordinated for delivery of intraoperative therapy, and after positioning of the device and approximation of the tissue, irradiation is accomplished in 20–35 min. Placement and treatment with the SAVI is usually accomplished as an outpatient. Currently, the INTRABEAM device is not available at most medical centers, and utility for other body sites has not been established. Many radiation facilities have the high-dose rate (HDR) afterloaders and shielded rooms necessary to deliver PBI. In addition, the HDR unit is useful for other body sites as well. Transport of either the HDR unit or the INTRABEAM device is not often possible or practical. Sparing of normal tissues with the INTRABEAM is accomplished in two ways. Because the output is 50 kV, dose fall-off is rapid and simple, and sterile lead shielding blocks the beam if necessary. For the same reason, close approximation of the target tissue is mandatory for accurate dose delivery and is accomplished on the operating table but without image guidance. Irradiation with an HDR unit uses ¹⁹²Ir, which emits photons in the energy range of 380 keV on average. Dose fall-off is more gradual, but the multiplicity of catheters allows outstanding dose modulation. Target tissue dose varies greatly between the two methods as well. APBI, first reported in 2000 with more than 5 years of median follow-up, delivered a dose of 34 Gy to the 1–2 cm of tissue surrounding the tumor bed [13]. Numerous studies, including one randomized prospective trial, have confirmed adequate local control with this dose, and singleentry devices such as the SAVI use the same tissue target and dose schedule. The TARGIT trial delivered 5–6 Gy at 1 cm in a single fraction and remains the only trial reported in PBI with this dose. While 4-year local control is reported, less than 50% of the population has been followed beyond 2 years and less than 33% beyond 3 years; therefore, the efficacy of this dose needs longer follow-up to assure control. However, there are reports postulating why this lower dose may be efficacious. One study published that the relative biological effectiveness of the 50-kV photons in a single dose may approach 1.5 but gives a similar relative biological effectiveness for 380 keV, so this would not explain a differential effect between these two methods [14]. Another study examined surgical wound fluid and noted that it stimulates tumor cell growth in vitro, and that with immediate irradiation, as in TARGIT, 3D growth, migration and invasion are relatively inhibited, but not eliminated [15]. While these observations may be true, only time will tell if PBI, using either the INTRABEAM or the single entry devices, is equivalent to WBI and adequate therapy for early-stage breast cancer, although there is significantly more data on APBI using a dose of 34 Gy.

Partial breast irradiation represents an advance in the development of adjuvant radiation therapy in the setting of breast conservation. The SAVI and INTRABEAM devices are unique forms of PBI with specific advantages and disadvantages. Further follow-up and evaluation of these and other forms of PBI are needed to better determine their appropriate clinical implementation.

Future perspective

The popularity of APBI is increasing, especially since the introduction of single-entry devices and the continued accumulation of data, although it is still immature. It is likely that its popularity will continue to increase as women choose a more accelerated course and less unnecessary normal tissue irradiation. New devices and methods, including single-dose intraoperative therapy, continue to be developed and explored, and trials are ongoing worldwide to evaluate the population of women with early-stage breast cancer who are most appropriate for PBI.

Financial & competing interests disclosure

Catheryn Yashar is a member of an advisory board for Cianna and has received research support and honoraria for speaking from Cianna. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

Catheryn Yashar is a member of an advisory board for Cianna and has received research support and honoraria for speaking from Cianna. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.