For women with early-stage breast cancer, breast-conserving therapy (BCT) is a well-established treatment option, comparable to total mastectomy with regard to rates of local-regional control and overall survival, yet enabling patients to maintain their breasts with acceptable cosmesis. Based on the initial trials conducted in the 1970s and 1980s, BCT has typically involved segmental mastectomy and some degree of lymph node surgery, followed by whole-breast irradiation (WBI) over the course of 5 weeks, with or without a “boost” treatment to the tumor bed. WBI is a relatively well-tolerated treatment that typically has resulted in good long-term cosmetic results, with low rates of treatment-associated morbidity. A meta-analysis published by the Early Breast Cancer Trialists’ Collaborative Group has demonstrated that the addition of radiation therapy (RT) to breast-conserving surgery has been found to improve not only local-regional control, but also long-term overall survival. Changing conventional radiation treatment to target only part of the breast must be scrutinized not only because of potential changes in local control but also on account of possible differences in overall survival when patients are followed for a long period of time.
The Rationale Behind APBI
Accelerated partial-breast irradiation (APBI) is an approach in which only the area of the breast where the tumor was initially located is targeted with radiation, with treatment typically delivered over 1 to 15 days. While WBI typically encompasses the breast parenchyma, chest wall musculature, ribs, and approximately 60% of the level I and II lymph nodes, APBI focuses radiation on a 1- to 2-cm margin of tissue surrounding the lumpectomy cavity (Figure 1). The rationale for irradiating only part of the breast stems from the observation that the majority of breast cancer recurrences following lumpectomy alone occur adjacent to the lumpectomy cavity, as evidenced by data from three randomized trials comparing treatment with lumpectomy alone with lumpectomy followed by WBI.[1,3,4] Indeed, in these studies, the incidence of treatment failures elsewhere in the breast, far from the initial tumor bed, occurred at the same rate in patients who received WBI as in those who did not, implying that the main local benefit of WBI is in the area of the tumor bed. Irradiating less of the breast would reduce dose to uninvolved breast tissue, the lungs, the ribs, the chest wall musculature, and the heart, all of which might reduce the risk of late complications.
Compared with a 5- to 6-week WBI treatment, it has been argued that the shorter course of APBI will improve patient satisfaction and overall quality of life, potentially minimizing the psychological and physical strain associated with radiation treatment.[6,7] For those patients who live far from a radiation oncology facility or who suffer from multiple medical comorbidities, a shorter treatment might improve compliance with completing the prescribed course of radiation and/or minimize the election of mastectomy over BCT.[8-12] Some recent analyses have highlighted that certain modalities of delivering APBI might also decrease the overall financial cost of treatment compared with WBI.[13-16]
APBI: Techniques and Clinical Outcomes
Multiple distinct treatment modalities have been used to deliver APBI, including brachytherapy, intraoperative techniques (x-rays, electrons), and external radiation with photons and/or protons. Each modality offers advantages and disadvantages, depending on patient anatomy and preference, as well as the resources available at a particular radiation oncology facility. Ideally, each patient is assessed for the technique that will best meet her individual needs.
Multicatheter interstitial brachytherapy
Multicatheter interstitial brachytherapy (MIB) is the APBI technique with the longest follow-up and the most mature data to support its use. MIB involves the placement of approximately 10 to 20 catheters in the breast tissue surrounding the lumpectomy cavity. This procedure can be performed under local anesthesia and is done only after final pathology results from the initial surgery have returned. Low or high dose rate radioactive sources are temporarily loaded into the catheters in a way that allows dose delivery to the tumor bed and a margin of 1 to 2 cm. Because of the properties of the radioactive sources used, MIB allows for highly conformal treatment, with near complete sparing of surrounding normal tissues.
The Radiation Therapy Oncology Group (RTOG) conducted a phase II, multi-institutional study, RTOG 95-17, which included 99 patients with early-stage breast cancer treated with APBI delivered via low or high dose rate brachytherapy. In this study, the 10-year rate of ipsilateral breast tumor recurrence (IBTR) was 6.2%, and half the recurrences were outside the area of the treatment field. Investigators at the National Institute of Oncology in Hungary have presented their 10-year follow-up of a randomized trial of 258 women randomly assigned to APBI or WBI, with APBI delivered either via MIB high dose rate (HDR) brachytherapy or external electron beam irradiation. The rates of recurrence were not significantly different between the two arms (5.9% for APBI vs 5.1% for WBI), and patients treated with APBI were found to have higher rates of good-to-excellent cosmesis (81% vs 63%, P = .009).
Detractors of this technique point to its invasiveness and the associated risk of infection and scarring. Among the prospective data published on interstitial brachytherapy used to deliver APBI, the rates of infection range from 0% to 11%, with the majority of studies citing rates < 5%.[19-22] Additionally, MIB requires a high degree of expertise on the part of both the physician and the physics staff, which is the primary reason it has not gained greater traction.
Single-entry intracavitary brachytherapy catheters
In response to growing clinical interest in APBI and the desire for a more easily implemented technique, intracavitary, single-entry brachytherapy catheters emerged as a way to deliver APBI using brachytherapy via an approach that is simpler for physicians and physicists and less traumatic for patients. A catheter is inserted through a puncture site in the breast and positioned within the lumpectomy cavity, typically under ultrasound guidance after surgery has been completed. At the completion of treatment, the catheter is removed with or without local anesthetic in the office. Unlike with MIB, early, single-lumen versions of the catheters used in single-entry brachytherapy were restricted to patients with specific geometric characteristics, ie, nonsuperficial surgical cavities. More recent multiple-lumen devices allow greater flexibility in treatment planning, enabling both better coverage of the target tissue at risk and decreased dose to the nearby rib and skin.
Since the US Food and Drug Administration (FDA) approved the original single-lumen MammoSite catheter in 2002, the use of brachytherapy is believed to have increased dramatically. A study of Medicare billing claims among women treated with BCT estimated that the use of brachytherapy as a component of oncologic care increased in incidence from less than 1% of cases in 2001 to 10% of cases by 2006. The American Society of Breast Surgeons has prospectively followed a cohort of 1,440 women treated with the single-lumen MammoSite catheter. This group has reported a 5-year actuarial IBTR rate of 3.8%. Of the patients in this study, 90.6% had good-to-excellent cosmesis, 13% developed symptomatic seromas, 9.5% developed an infection, and 2.3% developed fat necrosis, results comparable to those seen with MIB. More concerning have been the toxicities of brachytherapy-based APBI compared to those of WBI in population-based studies. Smith et al conducted a retrospective population-based cohort study of 92,735 women aged 67 or older with invasive breast cancer diagnosed between 2003 and 2007, treated with BCT, and followed through 2008. The study compared 6,952 women treated with brachytherapy vs 85,783 treated with WBI. The 5-year incidence of subsequent mastectomy was slightly higher among women treated with brachytherapy (4.0% vs 2.2%). It remains uncertain whether this difference in mastectomy rates was due to local recurrence (no data were available regarding the rate of local recurrence) or to toxicities that required surgical treatment, or to other unknown causes; it is also unclear whether this incremental difference negatively offsets the convenience of accelerated treatment. Brachytherapy was also associated with a higher rate of infectious and noninfectious complications, including breast pain, fat necrosis, and rib fracture. A follow-up study by Presley et al reported on 29,648 Medicare beneficiaries aged 66 to 94 treated with BCT between 2008 and 2009. There was a significantly higher rate of wound and skin complications among the 15.8% of women who received brachytherapy instead of WBI (adjusted rate of 33.7% vs 16.8%, P < .001), a rate that far exceeds anything published in the prospective literature. Notably, there was significant geographic variability in the frequency of treatment delivery with brachytherapy nationally, a finding also demonstrated in a Surveillance, Epidemiology, and End Results (SEER) database study looking at national trends. This finding implies that nonclinical factors influenced the implementation of brachytherapy-based APBI. These studies have the benefit of providing information about a broad cross section of patients treated throughout the United States, with large patient numbers. Deficits of these studies include, in most, a lack of information about clinical and tumor characteristics of the patients to whom treatment was given, making it difficult to ascertain whether treatment was given in a way that most would deem appropriate.
External beam irradiation
External beam irradiation, which can be delivered noninvasively, using the standard linear accelerator found in all radiation oncology facilities, is another way to deliver APBI. The RTOG published initial efficacy results from RTOG 03-19, a phase II, multi-institutional study using external beam irradiation to deliver APBI to 58 patients who have stage I/II breast cancer with tumors less than 3 cm in size and three or fewer involved lymph nodes, following segmental mastectomy with negative margins. The authors reported a 4-year IBTR rate of 6%, with two-thirds of these recurrences within the treatment field; 30% of patients developed grade 1/2 pain, and 4% (2 patients) developed grade 3 skin toxicities.
The preliminary toxicity results of a large Canadian cooperative group trial were presented at the annual meeting of the American Society of Radiation Oncology (ASTRO) in 2012. This trial randomly assigned 2,135 women aged 40 or older with early-stage breast cancer following BCT to either WBI or external beam, 3-dimensional conformal APBI. Cosmesis was assessed by the patient, physician, and a nurse, all of whom found the cosmesis at 3 years following completion of treatment was worse in the group treated with APBI (ie, by nursing assessment, poor-to-fair cosmesis in 32% of patients treated with APBI vs 19% of patients treated with WBI, P < .0001). Grade 1/2 late radiation toxicities were also worse in the group treated with APBI. It remains uncertain what the cause of this toxicity was and whether this finding will be replicated in the large pending trials comparing APBI with WBI; nonetheless, these findings should be of concern to those considering offering this treatment to patients.
Single-fraction, intraoperative radiation therapy has been investigated primarily in Europe as a way to deliver either monotherapy or boost radiation treatment at the time of lumpectomy.[33,34] The chief advantage of intraoperative radiotherapy is delivery of radiation precisely to the operative bed at the time of surgery, without any prolonged treatment or additional invasive procedures. However, this treatment is delivered without image guidance, and concerns have been raised that radiobiologic assumptions about dose escalation break down at such high doses per fraction. Also, margin status is not known at the time of surgery, and concerning pathology requires subsequent retreatment with additional radiation.
The Targeted Intra-Operative Radiotherapy (TARGIT-A) trial has published randomized controlled data on 2,232 patients in whom intraoperative kilovotage (kV) x-rays were used to target 1 cm away from the lumpectomy cavity, compared with WBI with or without a boost. Kilovoltage x-rays are considered to be more radiobiologically effective than the megavoltage x-rays used in traditional external beam RT; different forms of RT have been found in the laboratory to result in differential degrees of effect on such biologic endpoints as tumor cell kill or even damage to normal tissues, such as ribs. However, debate remains as to whether the dose prescribed is sufficient to provide tumor eradication that would be equivalent to what is provided by WBI or other forms of APBI. At 4 years, the rate of in-breast recurrence in TARGIT-A participants was equal in the two arms (1%).
Investigators in Milan recently presented their findings from the Electron Intraoperative Trial (ELIOT), in which 1,305 patients were randomly assigned to receive either WBI with a boost or intraoperative treatment with electrons. At 5 years, 3% of patients receiving APBI had a failure in the same quadrant as the primary tumor, compared with 1% of those treated with WBI. Breast failure elsewhere was 2% with APBI and 0% with WBI. With regard to toxicities, overall the patients treated with APBI did better than those treated with WBI, according to data presented at the 2012 World Congress of Brachytherapy; however, the detailed data have not yet been presented.
Protons offer another external modality for the delivery of radiation therapy that is noninvasive and that provides a sharper dose fall-off than photon- and electron-based external beam irradiation. The delivery of proton treatment is available at approximately a dozen sites internationally. Initial dosimetric analyses comparing protons to photon-based APBI demonstrated that the former provided comparable coverage of the target tissue at risk while decreasing the radiation dose delivered to the nontarget breast, lung, and heart. Unfortunately, the initial clinical publication from Massachusetts General Hospital reporting on 20 patients who were being followed revealed a relatively high rate of toxicities (22% of patients with moderate-to-severe moist desquamation at 6 to 8 weeks, 3 patients with telangiectasias, and 1 rib fracture, with a median follow-up of 12 months). In spite of this, 95% of patients reported satisfaction with their treatment. Investigators at Loma Linda have published their 4-year follow-up of a phase II study of 50 patients treated with APBI using protons. They reported a total of only 3 late grade 1 telangiectasias, and acute toxicities were grade 1/2 in half of the patients. It is unclear what caused the difference between these two studies, although there were differences in the beam arrangements used by these groups. Although facilities with the capability of delivering protons are currently limited in number, it is anticipated that many more such centers will be opening in the near future.
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