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Abstract

Breast-conserving therapy has been established as a standard treatment for women with early-stage breast cancer. Whole-breast irradiation has traditionally been utilized to consolidate local therapy following conservative surgery. Recently, the need for whole-breast irradiation after breast-conserving surgery has become controversial, with some investigators advocating accelerated partial breast irradiation as an alternative. Accelerated partial breast irradiation is delivered over a shorter period and only to a portion of the breast. This review will examine the emerging role of accelerated partial breast irradiation in the treatment of early-stage breast cancer and review the biologic rationale for, techniques of, and limitations of partial breast irradiation following breast-conserving surgery.

Keywords

accelerated irradiation brachytherapy breast cancer breast conservation MammoSite surgery

Breast-conserving therapy (BCT) has been established as a standard treatment for women with early-stage breast cancer. BCT, which consists of breast-conserving surgery and radiation therapy, results in survival equivalent to that observed after mastectomy alone [1 –9]. A recent 20-year follow-up from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial revealed a cumulative rate of recurrence in the ipsilateral breast of 14.3% in women with early-stage breast cancer who underwent lumpectomy and breast irradiation, compared with 39.2% in women who underwent lumpectomy without irradiation – thereby confirming the important role that radiation therapy plays in local disease control [10]. Numerous studies have also shown that conservative surgery and irradiation yield satisfactory cosmetic results [2,7,8,11 –15].

Recently, the need for whole-breast radiation therapy (WBRT) in BCT has been questioned, and some investigators have advocated accelerated partial breast irradiation (APBI) as an alternative. APBI is delivered over a shorter period than the standard 5–6 weeks of WBRT and is delivered to only a portion of the breast. Many health professionals believe that APBI holds the promise of a shorter treatment course, greater patient convenience, utilization of fewer resources, and improved cost effectiveness. Advocates of APBI argue that these advantages may increase the use of radiation therapy as a standard component of BCT for breast carcinoma. This review will examine the emerging role of APBI in the treatment of early-stage breast cancer and review the biologic rationale for, techniques of, and limitations of APBI following breast-conserving surgery.

Rationale for partial breast irradiation

The rationale for WBRT is to eradicate residual tumor foci that are present in the breast following breast-conserving surgery. There is evidence, however, that the overwhelming majority of in-breast recurrences occur in the quadrant of the breast from which the index tumor was excised. Indeed, data from a number of studies indicate that patients treated with lumpectomy alone have low rates of recurrence at remote sites within the breast and that their rates of remote-site recurrences are similar to the rates seen in patients treated with WBRT as part of BCT [16,17]. For example, in the NSABP B-06 trial, in which patients had histologically confirmed complete excision of the primary tumor, virtually all in-breast relapses in the nonirradiated group occurred in the index tumor quadrant [18]. An update of the NSABP B-06 trial demonstrated that 75% of local recurrences occurred at or near the lumpectomy site [19]. Other studies have similarly shown that when radiation is not given, the overwhelming majority of local recurrences after breast-conserving surgery occur at or near the lumpectomy site [1,3,7,8,20 –26]. On average, recurrences elsewhere in the breast occur in only approximately 3.3% of patients treated with lumpectomy alone (range: 0.6–5.8%) [1,3,7,8,20 –26]. Thus, the published data indicate that local relapse occurs overwhelmingly within the index tumor-bearing quadrant and that WBRT may not be necessary for unifocal early-stage breast cancer. APBI, therefore, may provide an equally efficacious, yet more convenient and cost effective, alternative to WBRT. There are several options for APBI, reviewed in the following sections.

Interstitial brachytherapy

One of the most utilized and investigated methods of APBI is brachytherapy. Brachytherapy permits the delivery of high radiation doses to small volumes, encompassing the tumor bed while sparing surrounding tissues, including the skin and lung. Brachytherapy has traditionally been delivered via multiple catheters that are implanted at the time of excision or re-excision or as a separate procedure. The radiation source is usually inserted into the catheters surrounding the tumor bed with automated afterloading technology. In the past, many large centers in both the USA and Europe utilized BCT that comprised breast-conserving surgery, WBRT and brachytherapy as an alternative to mastectomy. The primary role for brachytherapy was to provide a boost dose of radiation to the tumor-bearing quadrant after breast-conserving surgery and WBRT. Over the past decade, however, the use of brachytherapy as boost therapy has largely been abandoned, and most patients now receive a radiation boost with electron beams [27].

Brachytherapy has more recently been investigated for use as the sole radiation modality after breast-conserving surgery [28,29]. In this setting, brachytherapy is administered with either low-dose-rate (LDR) or high-dose-rate (HDR) radiation sources (Tables 1 & 2). With LDR brachytherapy, a dose of 45 to 50 Gy is delivered to the target volume at a rate of approximately 0.3 to 0.7 Gy/hour over 4 to 5 days in the in-patient setting. HDR brachytherapy, in contrast, can be performed on an outpatient basis and delivers a total dose of 34 Gy in twice-daily fractions of 3.4 Gy over 5 days.

Table 1.

Results of selected studies using low-dose-rate brachytherapy in the treatment of early-stage breast cancer.

Institution	No. of cases	Median follow-up (months)	Radiotherapy dose (cGy)	Local recurrence rate (%)	Ref.
Guy's Hospital	27	72	5500	37	[32,35]
Oschner Clinic	26	75	4500	2	[31]
William Beaumont	120	82	4992	1	[16]
Ninewells Hospital	11	72	4600–5500	0	[36]
Massachusetts General Hospital	48	23	5000–6000	0	[45]
Radiation Therapy Oncology Group 95–17	31	44	4500	0	[46 –48]
Florence	115	50	5000–6000	6	[69]

Table 2.

Results of selected studies using high-dose-rate brachytherapy in the treatment of early-stage breast cancer.

Institution	No. of cases	Median follow-up (months)	Radiotherapy dose (cGy)	Local recurrence rate (%)	Ref.
Oschner Clinic	26	75	3200	2	[31]
Ontario	39	91	3720	16	[30,40]
William Beaumont Hospital	79	52	3200	1	[16]
Radiation Therapy	68	44	3400	4	[46 –48]
Oncology Group 95–17
National Institutes of	45	84	4330–5200	7	[42,50,51]
Oncology, Hungary
Germany/Austria	176	12	5000	0.5	[70,71]
Royal Devon and Exeter	45	18	2000–3200	16	[33]
MammoSite RTS	43	21	3400	0	[55]

Most studies investigating implant brachytherapy as the sole method of radiation therapy are limited by small sample sizes and short follow-up [16,30 –34]. For example, in the first Guy's Hospital trial, 27 patients who had a single operable breast tumor were treated with a rigid iridium-192 implant inserted into the breast at the tumor excision site during surgery [35]. The implant delivered 55 Gy over 5 days. In that study, local in-breast relapses occurred in ten (37%) of the 27 patients. Such a high local relapse rate for implant brachytherapy would clearly be unacceptable given the 8% relapse rate with WBRT reported in the NSABP B-06 trial. However, in the Guy's Hospital trial, no attempt was made to achieve grossly or microscopically clear resection margins during resection of the primary breast tumor. In fact, 15 of the 27 patients had tumor involvement of the margin. On the other hand, a smaller study from Scotland [36], in which patients were more strictly selected, found no recurrences among 11 patients after 6 years of follow-up. Therefore, the high rate of local failure in the former study probably reflects poor study selection criteria and limited surgical excision, rather than inadequacy of implant brachytherapy.

A second Guy's Hospital study was conducted between 1990 and 1992 [37]. Patient selection criteria and surgical and implant techniques were similar to the first Guy's Hospital series except that [38]:

Only patients over the age of 40 were eligible

A cesium-137 afterloading device was used to give a total dose of 45 Gy in four fractions over 4 days

92% of the patients received some form of adjuvant systemic therapy

At a median follow-up period of 6.3 years, 18% of patients had developed a breast relapse with 78% of these recurrences being in the index quadrant.

More recent studies with strict enrollment criteria and defined dosimetric parameters have yielded much more promising results. In a prospective trial from the Ochsner Clinic, 52 patients with intraductal or invasive tumors at least 4 cm in diameter with at least three positive axillary nodes and negative inked surgical margins were treated with brachytherapy using either an LDR (45 Gy over 4 days) or HDR (32 Gy in eight fractions over 4 days) technique [31,39]. Only one recurrence (2%) in the treated breast and three regional nodal failures (6%) were reported. These results compared favorably with those in a historic control group treated with WBRT at the same institution over the same period. In a study from Ontario, Canada, Perera and colleagues also reported a low local recurrence rate for implant brachytherapy. In that study, 39 patients with clinical T1 or T2 breast cancer were treated with HDR brachytherapy (total dose of 37.2 Gy in 10 twice-daily fractions over 5–7 days) [30,40]. The 5-year actuarial rate of ipsilateral breast recurrence was 16% [40]. Of the six patients with ipsilateral recurrences, two had a recurrence within the lumpectomy site (in-field recurrences). One of these two patients had tumors cells within 1 mm of the margin at initial surgery; the other had a 1.5-cm, high-grade, infiltrating mammary carcinoma with no residual tumor upon wider resection at initial surgery. Four women developed invasive recurrences at least 1.6 cm from the lumpectomy site (out-of-field recurrences).

At the William Beaumont Hospital, 174 patients with Stage I or II breast cancer were treated with brachytherapy as the sole form of radiation therapy after breast-conserving surgery: 120 patients (69%) were treated with an LDR implant, and 54 (31%) were treated with an HDR implant [16]. No significant differences in the rates of locoregional failure, disease-free survival, or overall survival were found between patients treated with brachytherapy and a matched group of patients treated with conventional WBRT. A more recent study from the same institution examined a total of 199 patients with early-stage breast cancer who were treated prospectively with breast-conserving surgery and limited-field radiation therapy [41]. Five ipsilateral breast failures (i.e., recurrences) were observed in patients treated with limited-field interstitial brachytherapy. On matched-pair analysis with historic controls treated with WBRT, the rates of local recurrence did not differ significantly between the two patient groups [41,42].

Additional data on APBI can be derived from studies published by the Virginia Commonwealth University [43,44] and Massachusetts General Hospital [45]. In the Virginia Commonwealth trial 59 patients with a median tumor size of 1.1 cm had a median number of 15 needles implanted for APBI. At a median follow-up of 56 months, the 5-year local failure rate in the ipsilateral breast was 5.1% [43,44]. The study from the Massachusetts General Hospital reported no local recurrences following APBI; however, the median follow-up period was short (only 23 months) [45].

The Radiation Therapy Oncology Group (RTOG) Trial 95–17 [46 –48] was the first multi-institutional trial using interstial brachytherapy to deliver APBI. The trial sought to examine the feasibility, reproducibility, cosmesis, local control, and disease-free survival of patients who were treated with brachytherapy alone following lumpectomy and axillary lymph node dissection [49]. A total of 99 patients were accrued who met all eligibility criteria. The majority of patients had T1 tumors (87 patients). A total of 31 patients were treated with LDR brachytherapy (45 Gy given in 4.5 days) and 68 with HDR brachytherapy (34 Gy in ten fractions given over 5 days) [49]. With a median follow-up of 3.7 years, three patients developed a local recurrence. All three recurrences occurred in patients with T1 disease who had received HDR brachytherapy. The authors estimated that the 4-year actuarial in-breast recurrence was 3%.

There has been additional experience with brachtherapy for partial breast irradiation in Europe [38]. The National Institute of Oncology, Budapest, Hungary, investigated 45 patients with early stage invasive breast cancer treated using interstitial HDR implants between 1996 and 1998 [42,50,51]. Patients included in this study had tumors 2.0 cm or smaller, unifocal disease, pathologically negative lymph nodes, and microscopically negative surgical margins. A total of 30.3 or 36.4 Gy in seven fractions over 4 days was delivered. Recently, the 7-year follow-up of this study has been reported [42]. The actuarial rate of ipsilateral breast failure was 9%, not significantly different from patients who had received WBRT (12%) [42]. Disease-free and cancer-specific survival were also similar between the two groups.

A Phase III multicenter brachytherapy APBI protocol has recently been developed by the Breast Cancer Working Group of the European Society for Therapeutic Radiology and Oncology (ESTRO) [38]. Patients in the control group will be treated with 50–50.4 Gy of WBRT plus a 10 Gy boost versus interstitial HDR/pulsed-dose-rate brachytherapy in the experimental group. Eligibility criteria included age greater than 40 years, unifocal ductal carcinoma in situ or invasive carcinoma, tumor size 3 cm or smaller, no more than 1 micrometastases in the axillary nodes, and microscopically negative surgical margins [38]. The main hypothesis of the study is to investigate whether local tumor control after APBI is similar to that with standard WBRT. Secondary end-points include disease-free and overall survival, as well as cosmesis. Planned accrual is for 1170 patients [38].

Although initial published reports on the use of brachytherapy as the sole type of radiation therapy after breast-conserving surgery are promising, standard catheter-based interstitial brachytherapy has a number of disadvantages [31,52,53]. It is technically difficult, and only a limited number of clinicians in the USA are familiar with the technique. In addition, many patients and healthcare providers find the placement of catheters and the appearance of the multiple puncture sites required for insertion of traditional brachytherapy catheters disturbing. Given this, the widespread use of traditional brachytherapy has been limited. In contrast, there recently has been a large amount of interest in balloon-based intracavitary irradiation.

Balloon-based intracavitary brachytherapy

The MammoSite® radiation therapy system (RTS) device (Proxima Therapeutics, GA, USA) is a new balloon-based applicator that can be used to deliver breast brachytherapy after lumpectomy. The MammoSite device allows for insertion of an HDR radiation source at the center of an inflatable balloon. The device can be placed into the lumpectomy cavity at the time of surgery or after surgery when the definitive margin status is known. The MammoSite RTS device looks similar to a Foley catheter (Figure 1). It is 18.7 cm in length and approximately 0.6 cm in diameter and is available in two versions – one designed to be inflated to a diameter of 4–5 cm with a maximum inflation volume of 70 cm [3], and the other designed to be inflated to 5–6 cm with a maximum inflation volume of 125 cm [3]. The balloon is usually filled with normal saline combined with a contrast agent to allow for radiographic imaging to verify correct positioning. The MammoSite RTS device has an inflation channel and a central treatment channel that connects to a computerized afterloading device for delivery of the HDR radiation source. The MammoSite RTS device is pliable and can be worn within a bra, making it potentially more appealing to patients and clinicians than traditional brachytherapy applicators (Figure 2). Because of its simplicity and patient acceptance, balloon-based brachytherapy has been increasingly employed despite the lack of studies comparing its efficacy with that of standard postoperative external-beam irradiation.

Figure 1.

The MammoSite device.

Figure 2.

Implanted MammoSite device.

Reproducible placement of the MammoSite RTS device can be easily achieved, and although the mean dose homogeneity index has been shown to be less uniform than with traditional brachytherapy (0.77 and 0.93, respectively), the coverage of the planned target tissue is better (90 vs 69.8%) [54]. The prescribed radiation dose extends to 1 cm beyond the balloon when the balloon conforms to the lumpectomy cavity. The effective radiation penetration, however, may be closer to 2 cm as the balloon is inflated beyond the volume of the lumpectomy cavity, thereby stretching and thinning the surrounding tissue.

In one study investigating the MammoSite RTS device, 70 patients were enrolled in an eight-center prospective trial initially evaluating the safety and applicator performance of the MammoSite RTS device [55]. A dose of 34 Gy was delivered in ten fractions over 5 days prescribed to 1 cm from the balloon surface. A total of 16 patients did not have the MammoSite RTS device implanted because of a cavity that was too large, inadequate skin spacing (e.g. <7 mm), or final pathology findings. A total of 54 patients had the MammoSite RTS device placed, and 43 (80%) of these completed brachytherapy. The MammoSite RTS device was removed in the other 11 patients because of inadequate conformance to the cavity, pathologic findings, patient age and skin spacing [55].

The most common MammoSite RTS device-and radiation-related side effects are erythema, catheter-site drainage, breast pain and ecchymosis. When a seroma forms, catheter drainage is necessary in some patients to ensure that the balloon maintains contact with the lumpectomy cavity wall. Most complications are self-limiting and resolve without intervention, but occasionally a patient may develop an abscess that requires drainage.

No long-term follow-up data are available with respect to cosmesis or local control after treatment with the MammoSite RTS device. Although the US Food and Drug Administration (FDA) has approved the device for clinical use, a warning was issued stating that “the safety and effectiveness of the MammoSite RTS as a replacement for whole-breast irradiation in the treatment of breast cancer have not been established”. The indication for use of the MammoSite RTS device is to provide brachytherapy to deliver intracavitary radiation therapy to the surgical margins following lumpectomy for breast cancer. However, it is critical that the surgical community understand the important ethical and legal considerations that, at the minimum, need to be part of the informed consent process preceding treatment of patients with this new technique. The MammoSite RTS device might actually prove to be equivalent or similar to standard WBRT with respect to local control. However, this has yet to be proven in Phase III studies.

A study that will hopefully help to elucidate the role of the MammoSite RTS device is the ongoing MammoSite Patient Registry study sponsored by the American Society of Breast Surgeons. The MammoSite Patient Registry study is a multicenter, nonrandomized, prospective trial. The study objectives are to evaluate the efficacy of the MammoSite RTS device in patients with resected breast cancer and to evaluate the safety of the device. Primary end-points include disease-free survival, cause-specific survival, and ipsilateral and contralateral breast failure. Inclusion criteria include age greater than 45 years; T1, N0, M0 tumors; negative surgical margins; and a distance between the skin and balloon surface of no less than 7 mm. The study will enroll approximately 1300 patients.

Intraoperative radiation therapy

Delivery of a single dose of radiation at the time of surgery would be an extremely attractive alternative for patients undergoing lumpectomy for breast cancer. Intraoperative radiation therapy (IORT) has been utilized in patients with breast cancer to give an intraoperative boost dose of 9 Gy to the local tumor bed, followed by additional external-beam radiation therapy to the whole breast over 6 weeks [56]. More recently, some investigators have advocated the use of IORT as the sole method of radiation therapy following surgical extirpation of the tumor-bearing tissue. IORT has the advantages of being able to avoid the possibility of a geographic ‘miss’ and to avoid treatment of the skin so that cosmesis is improved.

IORT can be delivered using mobile linear accelerators, which are easily positioned near the operating table and have a movable arm that can be appropriately positioned for irradiation. Mobile linear accelerators usually have a variable spectrum of electron energy (3–10 MeV) and can be used in any operating room without structural modifications. Cylindrical applicators with diameters of 4–10 cm and terminal angles between 0° and 45° are used to achieve electron-beam collimation (Figure 3) [57]. For radioprotection, mobile shields (2-cm-thick lead) are positioned around and beneath the operating table. The patient, therefore, does not need to be transferred from the operating table. In general, using these devices, IORT is easy to perform and only slightly prolongs the surgical procedure. Before IORT administration, the breast tissue must be separated from the subcutaneous tissue for 2.5 to 4.0 cm around the wound, with care taken not to compromise the skin vascularity. The breast tissue must also be separated from the pectoralis fascia so that lead shields may be put between the breast and the pectoralis major muscle. Although this wide mobilization of the breast tissue slightly increases the total time of the operation, some surgeons have argued that it facilitates postresection reconstruction, which improves cosmetic results [58].

Figure 3.

Intraoperative radiation therapy for breast cancer utilizing a linear accelerate.

At the European Institute of Oncology, Milan, a study was initiated to investigate the feasibility of applying single doses of IORT of 10–22 Gy [59]. A portable IORT device with different electron energies was used to treat 65 patients with T1 or T2 (maximum diameter: 2.5 cm), N0 or N1 breast cancer. Patients receiving 10 Gy IORT were supplemented with 44 Gy WBRT. Patients receiving 15 Gy IORT also underwent 40 Gy of WBRT. WBRT was omitted at IORT dose levels of 17, 19, and 21 Gy [60]. The authors reported no acute side effects related to IORT and concluded that IORT is feasible and safe [59]. In another study by the same group, the authors reported that IORT was very well tolerated and that the majority of patients did not suffer skin erythema or fibrosis. Over the 1-year period of the study, the mean time needed to perform all the phases of IORT decreased from 40 to 20 min. This experience provides preliminary evidence that IORT is simple and rapid, that training staff to perform IORT is easy, and that acute side effects are minimal and not serious [61].

Recently, the group from Milan reported their experience with IORT using a specially designed mobile linear accelerator that can deliver four energy levels of electrons (3, 5, 7 and 9 MeV) via a head maneuvered by a robot arm (Figure 4) [62]. A total of 237 patients with breast cancers smaller than 2 cm in maximum diameter (T1) were studied. The majority of patients had undergone wide local excision with an axillary sentinel lymph node biopsy and then IORT. At a median follow-up of 19 months, the rate of post-treatment complications was very low. Only four patients (1.7%) developed breast fibrosis (mild in three patients and severe in one patient). Three patients (1.3%) developed ipsilateral breast cancer, two (0.8%) contralateral breast cancer, one (0.4%) supraclavicular metastasis, and one (0.4%) distant metastases [62]. This study provides further evidence that IORT with electron beams is technically feasible as well as minimally morbid. However, more long-term follow-up is needed before the efficacy of this technique can truly be known. This issue is being tested in the ELectron IntraOperative Treatment (ELIOT) trial.

Figure 4.

Targeted intraoperative radiation therapy.

The TARGeted Intraoperative radioTherapy (TARGIT) trial, initiated in the UK, is evaluating definitive IORT with low-energy x-rays as the sole form of radiation therapy after segmental mastectomy. With this approach, IORT is delivered utilizing a mini-electron-beam-driven x-ray source called Intrabeam (now Carl Zeiss). This device was approved by the FDA for radiotherapy in 1999. Low-energy x-rays (50 kV maximum) are emitted from the tip of a 10-cm long, 3.2-mm diameter probe that is enclosed in a spherical applicator (available in sizes ranging from 2.5 to 5.0 cm in diameter) that in turn is inserted into the tumor bed. IORT is delivered over 25 min [63]. The prescribed doses at 1 and 0.2 cm, respectively, are 5 and 20 Gy. Tungsten-impregnated rubber sheets are placed on the chest wall to protect the heart and lungs and placed over the wound to stop stray radiation, and the skin dose is monitored with thermoluminescent detectors. A randomized trial comparing IORT with the mini-electron-beam source to standard WBRT following lumpectomy for women with operable invasive breast cancer (T1 to T3, N0 or N1, M0) was initiated in March 2000 [64,101]. Several other centers in Europe, Australia and the USA are now collaborating to accrue patients on this trial, which will need to enroll approximately 1000 patients over the next 3–4 years to achieve the power to prove equivalence.

The use of the low-energy x-ray source has advantages as well as potential disadvantages related to dose attenuation. Because the biologically effective dose of radiation delivered by this source attenuates rapidly, specially designed operating rooms are not needed. However, the mini-electron-beam device has been criticized because the dose 1 cm from the margin is only 5 Gy, a dose that may be ineffective in eradicating occult carcinoma cells. The authors believe that a tumoricidal dose may be achieved only up to 2–3 mm from the x-ray source. Only the results of the randomized trial will tell if these theoretic concerns are real. The Milan group has been using larger doses of 21 Gy given as a single fraction with electrons. This dose has been criticized, however, because it is radiobiologically large, especially with respect to normal tissues. The adverse effects on normal tissues may also be further exaggerated with the Intrabeam device, given the very steep dose gradient between the prescription point in tissue and the surface of the applicator. However, the volume of normal tissues receiving the large single dose with this technique is small, so one may expect that the cosmetic outcome may be good [65].

3D conformal radiation therapy

3D conformal radiation therapy combines digital diagnostic imaging and post-imaging computer analysis to conform the radiation beam to the shape of the tumor. Treatment planning begins with computed tomography (CT) or magnetic resonance images that show the anatomy of the tumor and surrounding normal structures. These images are put into a treatment planning computer that produces an accurate 3D image of the tumor and surrounding organs so that multiple radiation beams can be aimed at the tumor from different directions, matching the contour of the treatment area. This delivers a prescribed dose across all three dimensions (height, width and depth) of the tumor and allows the dose to be spread around the surrounding normal tissue, minimizing the dose to any one area and sparing nearby healthy tissue. The potential advantages of 3D conformal radiation therapy include improved dose homogeneity within the target volume, which may improve cosmetic results and reduce the risk of symptomatic fat necrosis. In addition, although implant brachytherapy requires additional training and expertise, most radiation facilities already have the technologic tools required to deliver 3D conformal radiation therapy.

Formenti and colleagues recently reported on their experience using 3D conformal external-beam partial breast irradiation with the patient imaged and treated on a dedicated CT scanner [66]. In this study, the planned target volume included the tumor bed plus an additional 1- to 2-cm margin defined on a postlumpectomy CT scan. At a minimum follow-up of 36 months (range: 36–53 months), all patients were alive and disease-free with good-to-excellent cosmesis [66]. In Vicini and colleagues recent report of the William Beaumont Hospital experience utilizing 3D conformal external-beam partial breast irradiation after breast-conserving surgery in 31 patients [67], cosmetic results were rated as good to excellent in the majority of patients. In addition, the mean coverage of the planned target volume by the 95% isodose line was 100% (range: 97–100%). The authors concluded that 3D conformal radiation therapy is both technically feasible and associated with minimal acute toxicity.

One potential disadvantage of 3D conformal radiation therapy is that the breast moves with respiration and thus a larger volume of normal breast tissue may need to be irradiated to avoid a geographic miss of tumor-containing tissue. In a recent study by Baglan and colleagues, the impact of breathing motion on the clinical target volume in 3D conformal partial breast irradiation was investigated [68]. The authors found that 98–100% of the clinical target volume was covered by the 95% isodose line at the extremes of inhalation and exhalation when a 5-mm additional breathing margin was added to the planned target volume. The authors concluded that adding a 10-mm margin to the planned target volume would provide adequate coverage for most patients.

The Radiation Therapy Oncology Group recently completed a Phase II multicenter trial evaluating 3D conformal partial breast irradiation radiation, but the results of the trial have not yet been published.

Future perspective

Regardless of the method of delivery (IORT, implant or balloon brachytherapy, or 3D conformal radiation therapy), studies comparing APBI and standard WBRT with regard to long-term local control and disease-free survival are lacking. The American Society of Breast Surgeons has issued a consensus statement on APBI [102] that states that APBI should be performed only as part of an investigational protocol at an individual institution or as part of a multi-institutional trial (Box 1). This consensus statement outlines a number of criteria that may help guide selection of patients for trials. Toward this end, the NSABP B-39 study has recently been opened. This is a randomized Phase III study of conventional WBRT versus APBI for women with Stage 0, I, or II breast cancer (Figure 5). APBI will consist of multicatheter brachytherapy, MammoSite RTS brachytherapy, or 3D conformal external-beam radiation therapy. Patients requiring chemotherapy will receive it prior to WBRT or after APBI. The primary end point is in-breast tumor recurrence. Secondary end points are overall survival and disease-free survival. Eligibility criteria include a microscopically negative surgical margin, invasive or noninvasive breast cancer no larger than 3.0 cm, zero to three positive axillary lymph nodes, and a life expectancy of at least 10 years. The study is cosponsored by the Radiation Therapy Oncology Group and has been formally endorsed by the American College of Surgeons Oncology Group and the Southwest Oncology Group. Goal accrual for the study is 3000 patients.

Figure 5.

National Adjuvant Breast and Bowel Project randomized trial.

Box 1.

American Society of Breast Surgeons Consensus Statement on Accelerated Partial Breast Irradiation (APBI)

Data on APBI are neither extensive nor definitive. APBI should be performed as part of ongoing experimental protocols.

Patients should be carefully selected for APBI and be informed of the risks and benefits. The following selection criteria should be followed when considering patients for APBI in lieu of whole breast irradiation:-

– Age >50 years old

– Invasive ductal carcinoma or ductal carcinoma in situ

– Total tumor size <2 cm

– Microscopically negative surgical margins in all directions

– Axillary lymph nodes/sentinel lymph nodes negative

Both physician and radiation oncologist should follow patients closely to identify adverse events as well as local recurrences.

Current efforts should be directed toward enrolling appropriate candidates into large, randomized, prospective trials so that the efficacy of APBI with regard to local recurrence, survival, cosmesis and patient satisfaction can be more fully evaluated.

Executive summary

Rationale for partial breast irradiation

Whole-breast radiation therapy (WBRT) is used to eradicate residual tumor foci that are present in the breast following breast conservative surgery and generally takes 6 weeks of therapy.

The overwhelming majority of local recurrences after breast conservation surgery occur at or near the surgical excision site.

Accelerated partial breast irradiation (APBI) is given over a few minutes to a few days and only to the surgical site and may provide for an equally efficacious, yet more convenient and cost-effective alternative to WBRT.

Interstitial brachytherapy

Brachytherapy permits the delivery of high radiation doses to small volumes encompassing the tumor bed while sparing surrounding tissues, including the skin, lung for example.

Brachytherapy has traditionally been delivered using a complex implantation technique with multiple catheters placed within the breast.

Selected studies investigating brachytherapy reveal low rates of local recurrence, comparable to the recurrence rates seen after WBRT.

Long-term (5- to 7-year) results are available only with interstitial brachytherapy, proving that multicatheter brachytherapy with adequate patient selection and implant technique results in similar local tumor control to WBRT.

Balloon-based intracavitary brachytherapy

The MammoSite RTS device is a new balloon-based applicator that can be used to deliver breast brachytherapy after lumpectomy.

The MammoSite device may allow for a relatively simple method of insertion of the radiation source at the center of an inflatable balloon.

Several studies have shown that delivery of high-dose-rate radiation with the MammoSite device is feasible and safe.

No long-term follow-up data are available with respect to cosmesis or local control after treatment with the MammoSite brachytherapy catheter.

A study that should help to elucidate the role of the MammoSite RTS device is the MammoSite Patient Registry study sponsored by the American Society of Breast Surgeons, which is currently underway.

Intraoperative radiation therapy

Delivery of a single dose of radiation at the time of surgery for definitive local treatment can be achieved with intraoperative radiation therapy (IORT).

Preliminary evidence shows that IORT is simple, rapid, and that training staff to perform IORT is easy.

The acute side effects of IORT are minimal and not serious.

The use of IORT as the sole method of adjuvant radiation therapy following conservative breast surgery still needs to be validated in long-term studies evaluating local recurrence rates.

3D conformal radiation therapy

The potential advantages of 3D conformal radiation therapy include improved dose homogeneity within the target volume, which may improve cosmetic results and reduce the risk of symptomatic fat necrosis.

3D conformal radiation therapy is both technically feasible and associated with minimal acute toxicity.

The Radiation Therapy Oncology Group has recently completed a Phase II multicenter trial evaluating 3D conformal radiation, the results of this trial have not yet been published.

Whether 3D conformal radiation therapy yields the same long-term results as WBRT with regard to local and distant disease recurrence still needs to be investigated.

Future perspective

Regardless of the method of delivery (IORT, implant or balloon brachytherapy, or 3D conformal radiation therapy), randomized studies directly comparing APBI and standard WBRT with regard to long-term local and disease-free recurrence are lacking.

The American Society of Breast Surgeons (ASBS) has created a consensus statement on APBI that states that APBI should be performed as part of a protocol at an individual institution or in conjunction with multi-institutional trial groups.

The main randomized trials testing the concept of partial breast irradiation are the TARGeted Intraoperative radioTherapy (TARGIT) trial, ELectron IntraOperative Treatment (ELIOT) trial, Groupe Europeen de Curietherapie–European Society for Therapeutic Radiology and Oncology (GEC–ESTRO) trial, and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39. These trials mainly compare conventional whole breast irradiation versus partial breast irradiation for women with Stage 0, I or II breast cancer.

Large, randomized, prospective trials of APBI, supported by multiple cooperative trials, are necessary to confirm the toxicity of APBI as well as the short- and long-term efficacy of this technique with respect to local recurrence, survival, cosmesis and patient satisfaction.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

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Landmark trial results.

Sarrazin

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van Dongen

Bartelink

Fentiman

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Fourquet

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10.

Fowble

Solin

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12.

Fisher

Anderson

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13.

Classic study with 20-year follow-up of pivotal trial.

14.

Haffty

Goldberg

Fischer

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15.

Stotter

McNeese

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Oswald

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16.

Clarke

Edmundson

Martinez

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Vicini

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17.

Vicini

Recht

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18.

Abner

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Eberlein

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19.

Vicini

Baglan

Kestin

: Accelerated treatment of breast cancer. J. Clin. Oncol. 19, 1993–2001 (2001).

20.

Important paper, setting the stage for the recently opened National Surgical Adjuvant Breast and Bowel Project–Radiation Therapy Oncology Group randomized trial.

21.

Vaidya

Vyas

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Merchant

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Mittra

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22.

Fisher

Redmond

Poisson

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23.

Classic paper on the local therapy of breast cancer.

24.

Fortin

Larochelle

Laverdiere

Lavertu

Tremblay

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25.

Boyages

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26.

Clark

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27.

Liljegren

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Bergh

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28.

Touboul

Buffat

Belkacemi

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29.

Smith

Lee

Turner

Carter

Haffty

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30.

Important paper that defines the clinical course of patients with an ipsilateral breast cancer recurrence.

31.

Veronesi

Marubini

Mariani

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32.

Critically important trial results that have implications for the use of more conformal radiation techniques for breast cancer.

33.

Huang

Buchholz

Meric

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34.

Important paper that provides critical information on the clinical course of ipsilateral new-primary occurrence in patients treated with prior breast-conserving surgery and radiation.

35.

Shank

Moughan

Owen

Wilson

Hanks

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36.

Kuerer

Julian

Strom

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37.

Excellent general review on the subject, written by current experts in the local management of breast cancer. Good description of the newly opened US randomized study comparing whole breast radiation therapy to accelerated partial breast irradiation.

38.

Pawlik

Buchholz

Kuerer

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39.

Perera

Engel

Holliday

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40.

King

Bolton

Kuske

Fuhrman

Scroggins

Jiang

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41.

One of the largest single institution studies evaluating interstitial catheter-based radiation therapy.

42.

Fentiman

Poole

Tong

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43.

Clarke

Vicini

Jacobs

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44.

Martinez

Chen

Gustafson

: Irradiation of the tumor bed alone after lumpectomy with high dose rate brachytherapy. Proceedings of the 19th Annual Meeting of the American Brachytherapy Society. Palm Beach, FL, USA, 19–20 May 1997.

45.

Fentiman

Poole

Tong

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46.

Samuel

Dewar

Preece

Wood

RAB

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47.

Fentiman

Deshmane

Tong

Winter

Mayles

Chaudary

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48.

Polgar

Strnad

Major

: Brachytherapy for parital breast irradiation: the European experience. Semin. Radiat. Oncol. 15, 116–122 (2005).

49.

Kuske

Bolton

McKinnon

WMP

: 5-year results of a prospective phase II trial of wide-volume brachytherapy as the sole method of breast irradiation in Tis, T1, T2, N0–1 breast cancer (Abstr.). Int. J. Radiat. Oncol. Biol. Phys. 42, 181 (1998).

50.

Perera

Engel

: Patterns of breast recurrence in a pilot study of brachytherapy confined to the lumpectomy site for early breast cancer with 6 years' minimum follow-up. Int. J. Radiat. Oncol. Biol. Phys. 57, 1239–1246 (2003).

51.

Vicini

Kestin

Chen

Benitez

Goldstein

Martinez

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52.

Polgar

Major

Fodor

: High-dose-rate brachytherapy alone versus whole breast radiotherapy with or without tumor bed boost after breast-conserving surgery: 7-year results of a comparative study. Int. J. Radiat. Oncol. Biol. Phys. 60, 1173–1181 (2004).

53.

Vicini

Arthur

Polgar

Kuske

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54.

Arthur

Koo

Zwicker

: Partial breast brachytherapy after lumpectomy: low-dose-rate and high-dose-rate experience. Int. J. Radiat. Oncol. Biol. Phys. 56, 681–689 (2003).

55.

Critical paper in establishing the role and limitations of partial breast irradiation for breast cancer.

56.

Lawenda

Taghian

Kachnic

: Dose-volume analysis of radiotherapy for T1N0 invasive breast cancer treated by local excision and partial breast irradiation by low-dose-rate interstitial implant. Int. J. Radiat. Oncol. Biol. Phys. 56, 671–680 (2003).

57.

Kuske

Bolton

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58.

Kuske

Winter

Arthur

: A phase I/II trial of brachytherapy alone following lumpectomy for select breast cancer: toxicity analysis of Radiation Therapy Oncology Group 95–17. Int. J. Radiat. Oncol. Biol. Phys. 54, 87 (2002).

59.

Landmark prospective multicenter study trial.

60.

Kuske

Winter

Arthur

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61.

Vicini

Arthur

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62.

Polgar

Fodor

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63.

Polgar

Sulyok

Fodor

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64.

Foundation for further trials examining the use of partial breast irradiation for breast cancer.

65.

Wazer

Berle

Graham

: Preliminary results of a Phase I/II study of HDR brachytherapy alone for T1/T2 breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 53, 889–897 (2002).

66.

Watershed study that defined incidence and associations related to clinically evident fat necrosis following breast brachytherapy.

67.

Jewell

Krishnan

Reddy

Thomas

Mansfield

: Intraoperative implantation radiation therapy plus lumpectomy for carcinoma of the breast. Arch. Surg. 122, 687–690 (1987).

68.

Edmundson

Vicini

Chen

Mitchell

Martinez

: Dosimetric characteristics of the MammoSite RTS, a new breast brachytherapy applicator. Int. J. Radiat. Oncol. Biol. Phys. 52, 1132–1139 (2002).

69.

Keisch

Vicini

Kuske

: Initial clinical experience with the MammoSite breast brachytherapy applicator in women with early-stage breast cancer treated with breast-conserving therapy. Int. J. Radiat. Oncol. Biol. Phys. 55, 289–293 (2003).

70.

Initial report and landmark study evaluating a new brachytherapy delivery device.

71.

Reitsmaer

Peintinger

Sedlmayer

: Intraoperative radiotherapy given as a boost after breast-conserving surgery in breast cancer patients. Eur. J. Cancer 38, 1607–1610 (2002).

72.

Kuerer

Chung

Giovanna

: The case for accelerated partial-breast irradiation for breast cancer. Contemp. Surg. 59, 508–516 (2003).

73.

Intra

Gatti

Luini

: Surgical technique of intraoperative radiotherapy in conservative treatment of limited-stage breast cancer. Arch. Surg. 137, 737–740 (2002).

74.

Important report discussing the technique of intraoperative radiotherapy (IORT) for breast cancer.

75.

Gatzemeier

Orecchia

Gatti

Intra

Veronesi

: Intraoperative radiotherapy (IORT) in treatment of breast carcinoma – a new therapeutic alternative within the scope of breast-saving therapy? Current status and future prospects. Report of experiences from the European Institute of Oncology (EIO), Mailand. Strahlenther Onkol. 177, 330–337 (2001).

76.

Orrechia

Veronesi

: Intraoperative electrons. Semin. Radiat. Oncol. 15, 76–83 (2005).

77.

Veronesi

Orecchia

Luini

: A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated. Eur. J. Cancer 37, 2178–2183 (2001).

78.

Early report of IORT for breast cancer.

79.

Veronesi

Gatti

Luini

: Full-dose intraoperative radiotherapy with electrons during breast-conserving surgery. Arch. Surg. 138, 1253–1256 (2003).

80.

Vaidya

Baum

Tobias

Morgan

D'Souza

: The novel technique of delivering targeted intraoperative radiotherapy (TARGIT) for early breast cancer. Eur. J. Surg. Oncol. 28, 447–454 (2002).

81.

Important report evaluating the use of a new potential device to deliver IORT in breast cancer.

82.

Vaidya

Baum

Tobias

: Targeted intra-operative radiotherapy (TARGIT): an innovative method of treatment for early breast cancer. Ann. Oncol. 12, 1075–1080 (2001).

83.

Vaidya

Wilson

Houghton

: Cosmetic outcome after targeted intraoperative radiotherapy (TARGIT) for early breast cancer. Breast Cancer Res. Treat. 82, 1039 (2003).

84.

Formenti

Rosenstein

Skinner

Jozsef

: T1 stage breast cancer: adjuvant hypofractionated conformal radiation therapy to tumor bed in selected postmenopausal breast cancer patients – pilot feasibility study. Radiology 222, 171–178 (2002).

85.

Important study evaluating new techniques of conformal radiation therapy.

86.

Vicini

Remouchamps

Wallace

: Ongoing clinical experience utilizing 3D conformal external beam radiotherapy to deliver partial-breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy. Int. J. Radiat. Oncol. Biol. Phys. 57, 1247–1253 (2003).

87.

Important study that sets the stage for the US randomized trial of partial breast radiation.

88.

Baglan

Sharpe

Jaffray

: Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT). Int. J. Radiat. Oncol. Biol. Phys. 55, 302–311 (2003).

89.

Cionini

Marzano

Pacini

: Iridium implant of the surgical bed as the sole radiotherapeutic treatment after conservative surgery for breast cancer. Radiother. Oncol. 35(Suppl.), S1 (1995).

90.

Ott

Potter

Hammer

: Accelerated partial breast irradiation with iridium-192 multicatheter PDR/HDR brachytherapy. Preliminary results of the German–Austrian multicenter trial. Strahlenther. Onkol. 180, 642–649 (2004).

91.

Strnad

Ott

Potter

: Interstitial brachytherapy alone after breast conserving surgery: interim results of a German–Austrian multicenter Phase II trial. Brachytherapy 3(3), 115–119 (2004).

92.

www.thelancet.com/info/info.isa?n1=authorinfo&n2=Protocol+reviews&uid=9920

93.

Consensus statement for Accelerated Partial Breast Irradiation: www.breastsurgeons.org/officialstmts/officialstmt3.shtml (Accessed June 2005)

Accelerated Partial Breast Irradiation as an Alternative to Whole-Breast Irradiation in Breast-Conserving Therapy for Early-Stage Breast Cancer

Abstract

Keywords

Rationale for partial breast irradiation

Interstitial brachytherapy

Balloon-based intracavitary brachytherapy

Intraoperative radiation therapy

3D conformal radiation therapy

Future perspective

References