Ale

The Breast 21 (2012) 707e715

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Review

Accelerated partial breast irradiation: The need for well-defined patient selection criteria, improved volume definitions, close follow-up and discussion of salvage treatment Elizabeth C. Moser a, *, Conny Vrieling b a b

Breast Unit/Department of Radiotherapy, Champalimaud Cancer Centre, Lisbon, Portugal Centre d’Oncologie des Eaux-Vives, Geneva, Switzerland

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 June 2012 Received in revised form 17 August 2012 Accepted 23 September 2012

Breast-conserving therapy, including whole breast irradiation, has become a well-established alternative to mastectomy in early-stage breast cancer patients, with similar survival rates and better cosmetic outcome. However, many women are still treated with mastectomy, due to logistical issues related to the long course of radiotherapy (RT). To reduce mastectomy rates and/or omission of RT after breastconserving surgery, shorter, hypofractionated RT treatments have been introduced. More recently, the necessity of routinely treating the entire breast in all patients has been questioned, leading to the development of partial breast radiotherapy. With accelerated partial breast irradiation (APBI) these two approaches have been combined: the tumor bed with a 1e2 cm margin is irradiated either intraoperatively (single fraction) or postoperatively over 5e15 days. Different techniques have been developed, including interstitial brachytherapy, intra-cavity brachytherapy, intra-operative radiotherapy and external beam radiotherapy. These techniques are being evaluated in several ongoing phase III studies. Since its introduction, APBI has been the subject of continuous debate. ASTRO and GEC-ESTRO have published guidelines for patient selection for APBI, and strongly recommend that APBI be carried out within ongoing clinical trials. Recently, the patient selection criteria for APBI have also been up for debate, following the publication of results from different groups that do/do not confirm a difference in recurrence risk among the ASTRO defined risk groups. This paper reviews the different APBI techniques, current recommendations for patient selection, available clinical data and ongoing clinical trials. A case report is included to illustrate the need for careful follow-up of patients treated with APBI. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Accelerated partial breast irradiation Whole breast radiotherapy Interstitial brachytherapy Intra-cavitary brachytherapy Intra-operative radiotherapy External beam radiotherapy Permanent seed implant Patient selection guidelines Salvage treatment after partial breast irradiation

Introduction In order to reduce the time commitment and cost of breast radiotherapy, as well as to avoid potential overtreatment in breast cancer patients with a low local recurrence rate, new techniques of partial breast irradiation have been introduced to replace traditional whole breast radiotherapy (WBRT). However, breast conservative treatment (BCT) consisting of breast-conserving surgery (BCS) followed by WBRT is still the only treatment that has been proven to be as effective as mastectomy in early-stage breast cancer patients.1e7 Several trials and meta-analyses show that WBRT after BCS significantly reduces ipsilateral breast tumor recurrence (IBTR).1e7

* Corresponding author.

E-mail address: lottemoser@gmail.com (E.C. Moser).

0960-9776/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2012.09.014

The EBCTCG published a meta-analysis in 2005,1 showing a 5-year IBTR reduction from 26% to 7% and a 15-year breast cancer mortality reduction from 36% to 31%. However, excess mortality risk due to contralateral breast cancer (absolute excess risk (AER) 1.18), heart disease (AER 1.27) and lung cancer (AER 1.78) after radiotherapy (RT), overshadowed the survival benefit. The EBCTCG 2011 update confirmed a 10-year recurrence reduction from 35% to 19%, and importantly, demonstrated that local control matters: for every four recurrences prevented, one breast cancer death is avoided.6,7 Despite the proven efficacy of BCT, many women are still treated with mastectomy, due to logistical issues related to the long course of RT (time commitment, travel distances, limited radiotherapy resources, fears or treating physician’s bias).5,8e12 The elective WBRT approach is based on mastectomy studies showing tumor foci within 2 cm from the index tumor in 20% of patients and beyond 2 cm in 43% of patients.13,14 Gurdal et al.15

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demonstrated that more than 50% of re-excisions or mastectomies, performed because of close or positive margins, contained residual cancer. The presence of other foci is related to tumor margins, size, grade, histology (extensive intraductal component (EIC), lobular carcinoma), lymph node status and age.6,16e24 Recent reports indicate that foci are present mainly within a 1e2 cm margin, with skip lesions being rare.16,17 Unfortunately, the pathology data available thus far are still too limited to clearly identify the patients at risk of residual or multifocal breast disease.

Trials comparing BCS alone to BCS followed by WBRT have demonstrated that, in both treatment arms, most recurrences occurred close to the area of the tumor bed (67e85%).4,16 Furthermore, the number of recurrences further away in the ipsilateral breast, corresponded to the contralateral recurrence rate.17 More and more, both surgeons and radiation oncologists question the necessity of routinely treating the entire breast in all patients.16,17,25e27 Accelerated partial breast irradiation (APBI) refers to RT of a smaller (partial) breast volume over a shorter time interval, covering the tumor bed with a limited margin of normal tissue.29e 32 APBI can be delivered intra-operatively in a single fraction or postoperatively over 1e3 weeks; APBI significantly shortens treatment time and probably reduces mastectomy rates as well as health care costs.28e32 This paper reviews APBI techniques, current recommendations for patient selection, available clinical data and ongoing clinical trials. A case report illustrates the need for careful follow-up of patients treated with APBI. APBI techniques Interstitial brachytherapy33e41 With this technique, up to 20 catheters are inserted in the breast tissue surrounding the tumor cavity under direct visualization of the tumor bed during BCS. Radioactive sources are afterward loaded in the catheters to irradiate the cavity plus a 1e2 cm margin. High-, pulsed- or low dose rate brachytherapy can be used, with different dose and/or fractionation regimens. For high dose rate, the most frequently used schedule is 34 Gy in 10 fractions (twice daily) over 5 days. At the end of treatment, the catheters are removed.

Interstitial brachytherapy requires specialized, costly equipment and a high level of expertise, due to the relative complexity of the procedure. Dose heterogeneity within the target volume can potentially lead to fat necrosis and subcutaneous toxicity; however, this technique provides good sparing of heart and lung tissue.

Intra-cavity single-entry brachytherapy42e49 (MammoSiteÒ, AxxentÒ, ConturaÒ, SAVIÒ) These devices have been developed to simplify the interstitial brachytherapy procedure. An inflatable balloon attached to a single- or multi-lumen catheter is inserted into the surgical cavity, during BCS or afterward, using ultrasound guidance. The balloon is then inflated and a high dose rate radioactive source (commonly 192 Ir) is inserted. The balloon-to-skin distance should be 5e7 mm, with a shorter distance leading to a poorer cosmetic result.

Therefore, this technique might be less suitable for patients with small breasts or with tumors located in the upper, inner quadrant. The multi-lumen devices allow for dosimetric adaptation to improve target coverage and reduce dose to the ribs and skin. This technique provides good sparing of heart and lungs, but can also potentially lead to fat necrosis within the breast. The most

frequently used schedule is 34 Gy in 10 fractions (twice daily) over 5 days, prescribed to 1 cm from the balloon surface.

Intra-operative techniques (IORT) using X-rays or electrons50e53 (IntrabeamÒ, LiacÒ, MobetronÒ, or Novac-7Ò) IORT is used to deliver a single fraction (one-time treatment) in the operating room during BCS. The mobile IntrabeamÒ unit uses low-energy X-rays of 50 kV directed through an applicator sphere placed in the surgical cavity with breast tissue sutured around it.

The tumor bed, with no margin, is irradiated to a dose of 20 Gy in 20e45 min, with a dose fall-off to 5e7 Gy at 1 cm.

For the electron technique (LiacÒ, MobetronÒ, Novac-7Ò), a mobile linear accelerator producing 3e10 MeV electron beams is used in combination with an electron applicator. The applicator is placed over the surgical cavity, delivering a single fraction of 21 Gy to the tumor bed plus a margin of 1.5e3 cm.

Both techniques require dedicated equipment, operating room time and technical expertise. An important disadvantage of all intra-operative techniques is that histology of margins is not available at the time of treatment. Direct oncoplastic surgery,54 performed after dose application, can significantly improve cosmetic outcome, while not influencing the risk of geographical miss of the tumor bed.

External beam RT (EBRT)55e64 APBI can also be performed with the new generation linear accelerators that are already present in most RT departments.

Supine and prone patient positions have been tested, using threedimensional conformal EBRT. More conformal dose distributions can be obtained with intensity modulated radiotherapy, rotational techniques, tomotherapy, or the use of protons, giving better normal tissue sparing and target dose homogeneity. However, a larger volume outside the cavity receives a low dose, the longterm effects of which are not yet known. The most frequently used schedule is 38.5 Gy in 10 fractions (twice daily) over 5 days.

New techniques65e68 Other APBI techniques under evaluation in phase I and II trials are: permanent radioactive seed implants, and radiofrequency ablation. Permanent seed implant is an established treatment for prostate cancer that is now being tested for APBI. The invasive procedure involves the insertion of radioactive iodine or palladium seeds under ultrasound guidance with local anesthesia. The seeds deliver a dose of up to 90 Gy at a relatively low dose rate covering the defined target area (tumor cavity with a 15 mm margin).

Radiofrequency ablation is performed during BCS. A probe is placed in the tumor bed and heated for several minutes, creating a 1 cm ablation zone.

Selection criteria Because of the rapid increase in the use of APBI, combined with a lack of sufficient randomized trial data, both the American Society for Radiation Oncology (ASTRO) and the European GEC-ESTRO Cancer Working Group, have published guidelines for the implementation of APBI.69,70 The guidelines distinguish three categories of patients for determining suitability for APBI (Table 1): (1) low-risk or suitable group for whom APBI outside a clinical trial can be an acceptable treatment option; including patients >50 or 60 years, with unicentric, unifocal, small lesions (<3 cm),

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Table 1 Selection criteria according to ASTRO and GEC-ESTRO.

Age Tumor size Histology

Grade Pure DCIS EIC Associated LCIS Multicentricity Multifocality

Lymph-vascular invasion Estrogen receptor Surgical margins Lymph node status BRCA1/2 mutation Neoadjuvant therapy

ASTRO

GEC-ESTRO

ASTRO

GEC-ESTRO

ASTRO

GEC-ESTRO

Suitable

Low-risk

Cautionary

Intermediate-risk

Unsuitable

High-risk

60 years 2 cm Invasive ductal carcinoma or other favorable subtypes Any Not allowed Not allowed Allowed Unicentric only Clinically unifocal 2 cm

>50 years 3 cm Invasive ductal, mucinous, tubular, medullary and colloid carcinoma Any Not allowed Not allowed Allowed Unicentric only Unifocal

50e59 years 2.1e3.0 cm Invasive lobular carcinoma allowed

>40e50 years 3 cm Invasive lobular carcinoma allowed

<50 years >3 cm Any

40 years >3 cm Any

Any 3 cm 3 cm Allowed Unicentric only Clinically unifocal 2.1e3.0 cm

Any >3 cm >3 cm Allowed Multicentric Clinically multifocal

Not allowed

Not allowed

Limited/focal

Any Allowed Not allowed Allowed Unicentric only Multifocal (limited within 2 cm of the index lesion) Not allowed

Extensive

Any Any Allowed Allowed Multicentric Multifocal (>2 cm of the index lesion) Allowed

Positive 2 mm pN0 (i ,iþ) Not present Not allowed

Any 2 mm pN0 Not defined Not allowed

Negative Close (<2 mm) pN0 (i ,iþ) Not present Not allowed

Any Close (<2 mm) pN1mi, pN1a Not defined Not allowed

Any Positive pN1 Present If used

Any Positive pNx, pN2a Not defined If used

DCIS ¼ ductal carcinoma in situ; EIC ¼ extensive intraductal component; LCIS ¼ lobular carcinoma in situ.

non-lobular invasive breast cancer without EIC and lymphovascular invasion (LVI), with negative surgical margins (>2 mm) and without axillary node involvement (2) intermediate-risk or cautionary group, for whom APBI is considered acceptable only in the context of prospective clinical trials (3) high-risk or unsuitable group, for whom APBI is considered contra-indicated; patients 40e50 years of age or younger, with involved margins, and/or multicentric or large tumors, and/or presence of EIC or LVI, and/or >3 positive lymph nodes or unknown axillary status The ASTRO Task Force “strongly endorsed enrollment of all eligible patients considering APBI into prospective clinical trials to address many of the unanswered questions in APBI”.69 Ideally, the patients suitable for APBI would be determined according to the risk of clinically occult disease remote from the tumor bed. However, since these prognostic data are not available, the definition of the low-risk group was derived from the inclusion criteria and patient characteristics of published APBI trials. Most of the factors for the intermediate and high-risk groups are known prognostics for IBTR (close margins, young age, tumor size and grade, presence of EIC or lobular histology, LVI, axillary node positivity).5,16,18e24 However, other factors that may play an important role in IBTR are not part of the guidelines, such as HER2 amplification, proliferation index, biological subtype (basal cell versus luminal type) and (timing of) systemic treatment.71e75 Also, several gene expression patterns are being identified that provide added value to the conventional clinical tumor characteristics in predicting local recurrence after BCS.76e79 Nomograms have been developed to predict IBTR after BCS, using population-based datasets in the US (IBTR!)79 and clinical trial data in Europe.80 However, both nomograms were developed for WBRT and cannot justify an APBI-only approach.

The ASTRO and GEC-ESTRO criteria for the low-risk group are stricter than those recommended by the American Society of Breast Surgeons, who consider APBI to be a treatment option for patients over 45 years, with either invasive ductal carcinoma or ductal carcinoma in situ (DCIS) up to 3 cm in size, with clear margins and node negativity.81 The guidelines of the American Brachytherapy

Society mention APBI for patients of 50 years or older with a node negative, invasive ductal carcinoma up to 3 cm.82 Also, the inclusion criteria for some ongoing trials are less restrictive, e.g. the NSABP B-39/RTOG 0413 APBI trial83 accepts patients from 18 years of age, with either invasive adenocarcinoma or DCIS up to 3 cm, radically excised, and with no more than 3 axillary nodes positive.

Imaging Appropriate imaging is an important selection tool for APBI. The addition of ultrasound to mammography has improved detection of small breast cancers.84 Furthermore, magnetic resonance imaging (MRI) can detect multifocal cancer (22%) and/or contralateral breast involvement (5%) and results in a change of surgical approach in approximately 15% of patients.85e87 Al-Hallaq et al. showed that MRI performed in patients eligible for APBI found abnormalities outside the partial breast radiotherapy field in 10% of patients.88 Preoperative MRI confirmation of unicentric, unifocal breast lesions could play an important role in the selection process for APBI.89 Clinical target volume For successful APBI, a precise localization of the clinical target volume (CTV) is essential. Studies evaluating the accuracy of the boost irradiation as part of WBRT showed that contouring can differ among clinicians and that geographical misses are often observed.90,91 The tumor bed can be visualized either with ultrasound or a CT-scan, based on seroma or with the help of surgical markers.92,93 The CTV definition, however, is not straightforward.

Most studies define it as the tumor bed with a 1e2 cm margin. The margin size is a tradeoff between irradiation of too small a volume, resulting in under-dosage of areas at risk, and irradiation of an excessive volume, resulting in unnecessary fibrosis, fat necrosis and poorer cosmetic outcome.94e97 Prospective study material on the extension of microscopic disease related to CTV definition is rare, but can be very valuable when discussing margin reduction.98,99 The planning target volume (PTV) consists of the CTV plus a margin to correct for breathing motion and treatment set-up

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variability. To avoid toxicity, the PTV is limited to 5 mm from the skin and excludes the pectoral muscles.

Intra-operative APBI has the benefit of delivering the radiotherapy dose under direct visualization of the tumor bed, thus decreasing the possibility of geographical miss. However, optimal target volume definition is still not straightforward and safety margins vary among experts.50e53 Dose and fractionation schedule The most frequently used schedule for brachytherapy (either interstitial or intra-cavity single-entry brachytherapy) is 34 Gy in 10 fractions (twice daily) over 5 days.33e42 Although IORT is radiobiologically appealing with immediate cell kill after tumor excision with a single high dose, the biological equivalent dose (BED) of 1 20e21 Gy is lower than the classical WBRT treatment of 50 Gy followed by a 16 Gy boost.57,100,101 A single dose of 20e24 Gy has been described as ablative in lung, brain and other metastatic settings,102,103 but an optimal dose for breast lesions still has to be determined. Also, the tumoricidal effect of 21 Gy delivered with electrons cannot be directly compared to a dose of 20 Gy delivered using 50 kV photons.

In the published studies for external beam APBI many different fractionation schedules have been used, therefore, an adequate evaluation of the optimal dose needed for local control is difficult.

In the ongoing studies, the most frequently used EBRT schedule is 38.5 Gy in 10 fractions, twice daily over 5 days.55,58 Local control and toxicity Multi-catheter interstitial brachytherapy was the first technique used for APBI. Initial IBTR rates of 6e37% were reported.33,38 More recent studies, using stricter patient selection criteria and better quality assurance, show 5-year IBTR rates of 2.9e5%. Cosmetic evaluation varies with 56%e99% of patients reporting a good or excellent outcome.37,41 Shah et al. presented 12 years follow-up of 199 patients treated with interstitial brachytherapy, with an IBTR at 10 years of 5% compared to 4% in a matched population treated with WBRT.104 To facilitate the interstitial brachytherapy, several devices were introduced, of which the MammoSite is the most frequently used.48 The first results reported moderate cosmetic outcome in about 10e 25% of patients, related to the irradiated volume and the dose to the skin.44 IBTR rates seem promising in recent trials, but follow-up is short.43e49 A breast brachytherapy registry cohort is described by Vicini et al. In 1440 patients with a median follow-up of 4.5 years, the 5-year IBTR rate was 3.8% and 91% of patients had a good or excellent cosmetic result.45 Veronesi et al. reported the long-term experience of IORT with electrons: 1822 patients treated with 21 Gy, of whom only 1.9% showed mild or severe fibrosis and 4.2% fat necrosis. In these patients with small unicentric lesions (<2.5 cm) treated with quadrantectomy, the true local recurrence rate was 2.3% and the recurrence rate outside the treatment area was 1.3% (median follow-up of 3 years), leading to a total IBTR rate of 3.6%.50 Studies of APBI with EBRT also report good local control and excellent cosmetic outcome.55,105 With intensity modulated and rotational techniques, sparing of normal tissue has become easier.61e63 However, recently studies were published on unexpected toxicity.106e109 Jagsi et al.107 reported an early closure of an APBI study: 7 out of 34 patients (21%) treated with APBI (IMRT with deep-inspiration breath-hold) developed unacceptable cosmetic outcome. Hepel at al.108 reported on 60 patients treated with EBRT respecting the NSABP B-39/RTOG 0413 doseevolume constraints.

At 15 months, 10% of patients developed moderate-to-severe late

toxicity, especially subcutaneous fibrosis. Finally, Recht et al.109 reported 4 cases of pneumonitis in 29 patients (14%) treated with EBRT. Bentzen and Yarnold106 analyzed these reports and stated that the total dose could not explain the excess toxicity, since the equivalent dose of the applied schedules was around 52 Gy in 2-Gy fractions. The first uncertainty, however, related to the 6-h interval between daily fractions, since the interfraction recovery kinetics might be slower than estimated so far. Another important uncertainty concerned the doseevolume effect. The reports describing toxicity, however, did not use doseevolume parameters that were significantly different from those studies reporting good results.

Altogether, optimal and relevant dosimetric parameters and constraints are still to be determined.

Phase III trials in APBI e published and ongoing While trying to learn from the past, we have to underline the risk of retrospective subset analyses and the bias introduced when comparing recent studies to older ones; definite conclusions on safety and outcome should be based on randomized trial data.110 So far, only 4 Phase III randomized trials and one meta-analysis evaluating APBI have been published. Three of these studies have important limitations: The Yorkshire Breast Cancer Group trial111 failed to complete accrual and used a variety of techniques. The Christie Hospital trial,112 randomizing 708 patients between APBI and WBRT, lacked appropriate target volume definition criteria and entered many patients outside the ‘low-risk group’. The Hungarian trial113 compared WBRT with APBI using HDR implants or electrons (normal fractionation) in 258 women with margin negative, earlystage breast cancers. The study was unfortunately stopped due to a competing trial, and therefore lacks sufficient sample size. A meta-analysis of these Phase III trials was presented at ASCO in 2009 and published in 2010.114 Compared to WBRT, APBI was associated with an increased risk for both local (pooled odds ratio (OR) 2.15; p ¼ 0.001) and regional recurrence (pooled OR 3.43; p < 0.001), however not (yet) translating in a survival difference (OR 0.91; p ¼ 0.55).114 The first randomized controlled trial that provides level I evidence is the TARGIT trial published in 2010.51 A total of 2232 patients were randomly allocated to WBRT or IORT (20 Gy with 50 kV Intrabeam). The dose was prescribed to the cavity surface, attenuating to 5e7 Gy at 1 cm depth. Patients aged 45 years or older with unifocal invasive ductal carcinoma according to conventional imaging were eligible. Fourteen percent of patients received WBRT following intra-operative RT due to unfavorable histological features. With a median follow-up of 2 years, the estimated 4-year local recurrence rate was 0.95% in the WBRT group and 1.2% in the TARGIT group (p ¼ 0.41). Neither complication nor toxicity rates differed between the two groups.

The results of seven randomized Phase III trials are awaited (Table 2).83,115e120 Three of these studies have completed accrual.117,118,120 The first results of the ELIOT trial have been presented earlier this year, alerting a higher IBTR rate in the IORT arm.121 A direct comparison of APBI techniques is not part of any trial.

Results with follow-up over 5 years will not be available until 2017, hopefully not only providing information regarding the long-term efficacy and safety of APBI, but also regarding adequate patient selection and doseevolume constraints.

Case report With the increasing use of APBI, we are confronted with a new clinical dilemma: what to do in the event of IBTR. To illustrate this

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Table 2 Prospective Phase III APBI trials.

Trial

N

Inclusion criteria

Control arm

Experimental arm

Activated

NSABP B-39/RTOG 041385

4300

WBRT 50 Gy in 25e28 fractions boost

Interstitial brachytherapy or MammoSite 34 Gy in 10 fractions in 5e10 days or 3D EBRT 38.5 Gy in 10 fractions in 5e10 days

2005 (accrual now closed to low-risk patients)

RAPID/Ontario Clinical Oncology Group119

2128

WBRT 42.5 Gy in 16 fractions for small breasts or 50 Gy in 25 fractions for large breasts boost

3D EBRT 38.5 Gy in 10 fractions in 5e8 days

2006

GEC-ESTRO120

1233

WBRT 50 Gy in 25e28 fractions boost

Interstitial brachytherapy 32 Gy in 8 fractions HDR, 30 Gy in 7 fractions HDR, 50 Gy PDR

2004e2009

IMPORT LOW121

1935

18 years, Stage 0eII, (T < 3 cm), DCIS or invasive adenocarcinoma, 3 Nodes positive, Margin negative 40 years, T < 3 cm, DCIS or invasive carcinoma, Node negative, Margin negative, No BRCA1 or 2 40 years, Stages 0eII (T 3 cm), DCIS or invasive adenocarcinoma, Node negative or with micro-metastasis Margin 2 mm 50 years, T 3 cm, Invasive adenocarcinoma (not lobular), Node negative, Margin 2 mm

WBRT 40 Gy in 15 fractions in 21 days

2007e2010

ELIOT122

1306

WBRT 50 Gy in 25 fractions boost

EBRT (IMRT) Arm 1: 40 Gy in 15 fractions to primary tumor region þ 36 Gy in 15 fractions to low-risk region Arm 2: 40 Gy in 15 fractions to primary tumor region IORT 21 Gy in 1 fraction, electrons up to 9 MeV

IRMA123

3302

WBRT 45 Gy in 18 fractions or 50 Gy in 25e28 fractions

3D EBRT 38.5 Gy in 10 fractions in 5 days

2007

SHARE124

2796

WBRT Arm 1: 40e42.5 Gy in 15e16 fractions Arm 2: 50 Gy þ 16 Gy boost in 33 fractions

3D EBRT 40 Gy in 10 fractions in 5e7 days

2010

48 years, T 2.5 cm, Invasive carcinoma, Node negative 49 years, T < 3 cm, Invasive carcinoma, 3 Nodes positive, Margins 2 mm 50 years, T 2 cm, Invasive carcinoma, Node negative, Margins <2 mm

2000e2007

T ¼ tumor size; DCIS ¼ ductal carcinoma in situ; WBRT ¼ whole breast irradiation; boost ¼ extra dose to the tumor bed; EBRT ¼ external beam conformal radiotherapy; HDR ¼ high dose rate; PDR ¼ pulsed dose rate; IMRT ¼ intensity modulated radiotherapy; IORT ¼ intra-operative radiotherapy; 3D EBRT ¼ tridimensional conformal external beam radiotherapy.

decision-making process, we present the case of a patient recently seen in our clinic.

A 57-year-old patient presented seeking a second opinion for a local recurrence 5 years after IORT (20 Gy with electrons) for a 5 mm invasive ductal carcinoma of her left breast. She was treated with Tamoxifen for 2 years, but had stopped because of joint pain and vaginal dryness. An MRI, performed because of uncertainty on mammography regarding scar tissue, showed a new 7 mm lesion, about 1 cm from the initial APBI site. Her treating physician proposed to repeat the MRI in 6 months time and, in case of growth, to re-treat her with BCS and APBI, because of perfect cosmetic outcome of the first intervention. She opted for a second opinion. It was advised to perform an ultrasound-guided biopsy that showed the same histology as in 2007: estrogen receptor and HER2 positive invasive ductal carcinoma, grade 2.

FDG PET-CT fixed in the breast and in one left axillary and two small left parasternal lymph nodes.

Although breast-conserving surgery seemed possible given the size of her breast, the patient stated her strong wish for definitive local control and symmetric cosmetic outcome. We proposed to perform a mastectomy with immediate reconstruction, excision of

the axillary and parasternal nodes and reduction of the right breast.

A mastectomy would allow us to estimate distant foci and achieve complete staging of the disease. Final histology showed two similar lesions less than 1 cm away from the fibrosis of the former APBI and axillary and parasternal metastases. The patient has started adjuvant treatment consisting of chemotherapy, loco-regional external RT, anti-HER2 and hormonal treatment.

In this case, the role of imaging is clear, showing more advanced disease than initially suspected. Retreatment with BCS and APBI would have undertreated the extent of tumor present, both in terms of surgery and RT. The final cosmetic outcome was good with direct intervention of the plastic surgeon.

Discussion Additional RT after BCS is an effective means of lowering the risk of IBTR.1e6 However, while the role of classical WBRT in BCT is well defined, this is not the case for the shorter treatment course alternatives that have been introduced so that more patients may benefit from RT. Because of the shorter time commitment and the decrease in travel time and costs, APBI has become a very attractive

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treatment option. It is estimated that so far more than 50,000 patients have been treated with MammoSite in the USA.122 However, there are still outstanding issues including, importantly, patient selection. ASTRO and GEC-ESTRO guidelines are based on inclusion criteria and patient’s characteristics of published prospective single-arm APBI trials.71,72 However, it remains unclear if these guidelines optimally define the risk categories.

Shaitelman et al. published an evaluation of 1449 patients enrolled in the MammoSite Registry Trial, classified according to the three risk groups defined by ASTRO.123 They found that IBTR at 5 years was not significantly different in the three groups (the local recurrence rate for the suitable, cautionary and unsuitable group was 2.6%, 5.4% and 5.3%, respectively, p ¼ 0.19). The main limitation of this study, however, was that many important histological factors were unknown (e.g. data on multifocality, multicentricity, LVI, histology of invasive cancer, BRCA1/2 mutation). Other studies (with limited patient numbers) from the same institution showed that the risk of local recurrence was not increased in patients with triple negative receptor status, invasive lobular cancer and node positivity, treated with APBI.124,125 The outcome for 136 patients, meeting the ASTRO cautionary criteria, treated with HDR brachytherapy APBI was published McHaffie et al.126 The 5-year IBTR rate was 4.8%. However, among the 104 patients with invasive carcinoma, the IBTR rate was 0% in patients considered ‘cautionary’ due to age alone versus 13% in patients considered cautionary due to pathological factors (p ¼ 0.02).

The Milan group evaluated 1822 patients treated with IORT (electrons) outside their randomized study according to the ASTRO consensus statement. 294 patients were classified as suitable, 691 patients as cautionary and 812 patients as unsuitable (25 patients could not be classified). These patients had a 5-year IBTR rate of 1.5%, 4.4% and 8.8%, respectively (p < 0.001).127 The IBTR in the suitable patients is so low, that one of the future questions that should be addressed is: do these patients need radiotherapy at all?

Clinical practice shows that many of the patients treated with APBI outside clinical trials do not conform to criteria of the low-risk group.123,127,128 Husain et al. published a patterns-of-care analysis of 4172 patients treated with MammoSite between 2002 and 2007.128 The use of APBI brachytherapy increased almost 10-fold in this time period; 38% of patients were characterized as suitable, 44% as cautionary and 18% as unsuitable according to the ASTRO consensus.

It can be concluded that it is not clear whether patients not fitting the suitable criteria have a higher IBTR rate (as suggested by the Milan group but contradicted by the MammoSite Registry Trial).123,125,126 This is a concern, since the majority of patients treated with APBI in clinical practice do not fit the criteria for the suitable group, but they are not being included in clinical trials.126 The ongoing clinical trials will hopefully provide some answers for patient selection, including an improved selection based on molecular and genetic profiling. Gene expression patterns that provide added value to the conventional clinical tumor characteristics in predicting local recurrence after BCS may play an important role in the patient selection process.74e78 However, the IBTR rate in current trials tends be so low that the APBI trials might not be able to detect differences simply because of lack of events and the need for very long follow-up. The NSABP B-39/RTOG 0413 trial so far accrued mainly low-risk patients, and therefore has now restricted accrual to high-risk patients (younger than 50 years of age with DCIS or invasive breast cancer with any receptor status and either N0 or N1; or older than 50 years of age with invasive breast cancer, hormone receptor negative, either N0 or N1, or hormone receptor positive and N1), in order to be able to clarify adequate patient

selection criteria. The results, however, will not be available for another 5e8 years.83 Another issue is the need for a clear definition of the CTV and the dose to be delivered. As concluded by Mannino and Yarnold,129 “the most important difference between the APBI trials relates to the size of the partial breast PTV, which is the lowest in the TARGIT trial and the largest in the IMPORT LOW trial.” With differences ranging from a few cc (TARGIT) up to 300 cc (EBRT), it is hard to compare efficacy and toxicity. For an adequate CTV definition, more pathological studies are needed to determine the extension of microscopic disease. Histological data can help in individualizing margins and the choice of treatment technique, according to patient risk factors.

A third important and still unanswered issue relates to the IBTR rate and management following APBI. The case report presented above described patient with a pT1a, pN0 invasive ductal carcinoma, presenting 5 years after APBI with locally advanced disease.

The initial tumor, being HER2 positive, should be classified as biologically aggressive, for which APBI might not be the best option.

Furthermore, it was the patient herself demanding the breast MRI and FDG PET scan, showing far more extensive disease than initially suspected. These results show the key role of imaging in the staging of a local recurrence after APBI and the need for staging and salvage guidelines.

At the San Antonio Breast Cancer Symposium 2011, an MD Anderson study was presented and recently published in the JAMA, analyzing five-year results in 130,535 older Medicare breast cancer patients treated with APBI brachytherapy versus WBRT. This survey reports the increasing use of APBI from less than 1% in 2000 up to 13% of patients treated in 2007. IBTR data were not available; therefore, cumulative incidence of subsequent mastectomy was analyzed as a surrogate for local failure. The 5-year cumulative incidence of subsequent mastectomy was significantly higher in patients treated with APBI than WBRT (4.0% versus 2.2%, respectively, p < 0.001).

APBI was also associated with higher acute (e.g. infection: 16.2% versus 10.3%, p < 0.001) as well as late complication rates (e.g. fat necrosis: 8.3% versus 4.1%, p < 0.01).130,131 Although the data were collected in a retrospective, non-randomized way, it is clear that too many patients are treated today with APBI outside clinical trials. An eventual increase in IBTR in this population will be neither easily detected, nor well documented.

From the EBCTCG meta-analysis6,7 we know that local control matters: an increase in local recurrence rate translates into an increase in 10-year breast cancer deaths. For the coming years, with the results from the randomized trials not yet available, ABPI should be used with caution, with careful patient selection and accurate documentation of follow-up and occurring events.

Conclusion APBI has become a strong player in the field of postoperative radiotherapy after BCS. However, optimal selection criteria for a personalized RT approach are still far from well defined. In about 5e8 years, the ongoing studies will hopefully answer the questions related to patient selection, long-term outcome, and toxicity of the different techniques. It should be noted that the far majority of APBI patients are treated outside of clinical trials, do not fit the criteria of the suitable patient group and are not systematically followed.

Without proper evaluation and registration of these patients, an increase in IBTR rate will go unnoticed. A modest reduction in initial treatment efficacy cannot be justified in patients with early breast cancer, who have an excellent prognosis with standard BCT including WBRT. For the coming years, patients should be carefully selected for APBI and closely followed with accurate documentation of any occurring events.

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References 1. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087e106.

2. Litière S, Werutsky G, Fentiman IS, Rutgers E, Christiaens MR, Van Limbergen E, et al. Breast conserving therapy versus mastectomy for stage IeII breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial. Lancet Oncol 2012;13:412e9.

3. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al.

Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. New Engl J Med 2002;347:1233e41.

4. Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al.

Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. New Engl J Med 2002;347:1227e32.

5. Vinh-Hung V, Voordeckers M, Van de Steene J, Soete G, Lamote J, Storme G. Omission of radiotherapy after breast-conserving surgery: survival impact and time trends. Radiother Oncol 2003;67:147e58.

6. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)Darby S, McGale P, Correa C, Taylor C, Arriagada R, et al. Effect of radiotherapy after breastconserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707e16.

7. Recht A, Solin LJ. Breast-conserving surgery and radiotherapy in early-stage breast cancer: the importance of local control. Semin Radiat Oncol 2011;21:3e9.

8. Nattinger AB. Variation in the choice of breast-conserving surgery or mastectomy: patient or physician decision making? J Clin Oncol 2005;23: 5429e31.

9. Schroen AT, Brenin DR, Kelly MD, Knaus WA, Slingluff Jr CL. Impact of patient distance to radiation therapy on mastectomy use in early-stage breast cancer patients. J Clin Oncol 2005;23:7074e80.

10. Hershman DL, Buono D, McBride RB, Tsai WY, Joseph KA, Grann VR, et al.

Surgeon characteristics and receipt of adjuvant radiotherapy in women with breast cancer. J Natl Cancer Inst 2008;100:199e206.

11. Athas WF, Adams-Cameron M, Hunt WC, Amir-Fazli A, Key CR. Travel distance to radiation therapy and receipt of radiotherapy following breast-conserving surgery. J Natl Cancer Inst 2000;92:269e71.

12. Fong A, Shafiq J, Saunders C, Thompson AM, Tyldesley S, Olivotto IA, et al.

A comparison of surgical and radiotherapy breast cancer therapy utilization in Canada (British Columbia), Scotland (Dundee), and Australia (Western Australia) with models of “optimal” therapy. Breast 2012;21:570e7.

13. Holland R, Veling SH, Mravunac M, Hendriks JH. Histologic multifocality of Tis, T1e2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985;56:979e90.

14. McCormick B, Kinne D, Petrek J, Osborne M, Cox L, Shank B, et al. Limited resection for breast cancer: a study of inked specimen margins before radiotherapy. Int J Radiat Oncol Biol Phys 1987;13:1667e71.

15. Gurdal SO, Karanlik H, Cabioglu N, Ozcinar B, Yavuz E, Tuzlali S, et al. Positive or close margins in breast conserving surgery: is re-excision always necessary? Eur J Surg Oncol 2012;38:399e406.

16. Vaidya JS, Vyas JJ, Chinoy RF, Merchant N, Sharma OP, Mittra I. Multicentricity of breast cancer: whole-organ analysis and clinical implications. Br J Cancer 1996;74:820e4.

17. Goldstein SN. Controversies in pathology in early-stage breast cancer. Semin Radiat Oncol 2011;21:20e5.

18. Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 2004;96:115e21.

19. Fisher ER. Pathobiological considerations relating to the treatment of intraductal carcinoma (ductal carcinoma in situ) of the breast. CA Cancer J Clin 1997;47:52e64.

20. van de Water W, Markopoulos C, van de Velde CJ, Seynaeve C, Hasenburg A, Rea D, et al. Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer.

JAMA 2012;307:590e7.

21. Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al.

Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 2008;26:2373e8. Erratum in: J Clin Oncol 2008; 26: 3110.

22. Jones HA, Antonini N, Hart AA, Peterse JL, Horiot JC, Collin F, et al. Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial. J Clin Oncol 2009;27:4939e47.

23. Peiro G, Bornstein BA, Connolly JL, Gelman R, Hetelekidis S, Nixon AJ, et al. The influence of infiltrating lobular carcinoma on the outcome of patients treated with breast-conserving surgery and radiation therapy. Breast Cancer Res Treat 2000;59:49e54.

24. Arvold ND, Taghian AG, Niemierko A, Abi Raad RF, Sreedhara M, Nguyen PL, et al. Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol 2011;29:3885e91.

713

25. Ali AN, Vapiwala N, Guo M, Hwang WT, Harris EE, Solin LJ. The impact of re-excision and residual disease on local recurrence after breast conservation treatment for patients with early stage breast cancer. Clin Breast Cancer 2011;11:400e5.

26. MacDonald S, Taghian AG. Prognostic factors for local control after breast conservation: does margin status still matter? J Clin Oncol 2009;27:4929e30.

27. Halyard MY, Wasif N, Harris EE, Arthur DW, Bailey L, Bellon JR, et al. Expert panel on radiation oncology-breast: ACR Appropriateness CriteriaÒ localregional recurrence (LR) and salvage surgery: breast cancer. Am J Clin Oncol 2012;35:178e82.

28. Njeh CF, Saunders MW, Langton CM. Accelerated partial breast irradiation (APBI): a review of available techniques. Radiat Oncol 2010;5:90.

29. Sanders ME, Scroggins T, Ampil FL, Li BD. Accelerated partial breast irradiation in early-stage breast cancer. J Clin Oncol 2007;25:996e1002.

30. Biagioli MC, Harris EE. Accelerated partial breast irradiation: potential roles following breast-conserving surgery. Cancer Control 2010;17:191e204.

31. Lehman M, Hickey B. The less than whole breast radiotherapy approach.

Breast 2010;19:180e7.

32. Lievens Y. Hypofractionated breast radiotherapy: financial and economic consequences. Breast 2010;19:192e7.

33. Polgár C, Major T, Fodor J, Németh G, Orosz Z, Sulyok Z, et al. High-dose-rate brachytherapy alone versus whole breast radiotherapy with or without tumor bed boost after breast-conserving surgery: seven-year results of a comparative study. Int J Radiat Oncol Biol Phys 2004;60:1173e81.

34. Chen PY, Vicini FA, Benitez P, Kestin LL, Wallace M, Mitchell C, et al. Long-term cosmetic results and toxicity after accelerated partial-breast irradiation: a method of radiation delivery by interstitial brachytherapy for the treatment of early-stage breast carcinoma. Cancer 2006;106:991e9.

35. Johansson B, Karlsson L, Liljegren G, Hardell L, Persliden J. Pulse dose rate brachytherapy as the sole adjuvant radiotherapy after breast-conserving surgery of T1eT2 breast cancer: first long term results from a clinical study.

Radiother Oncol 2009;90:30e5.

36. Kaufman SA, DiPetrillo TA, Price LL, Midle JB, Wazer DE. Long-term outcome and toxicity in a Phase I/II trial using high-dose-rate multicatheter interstitial brachytherapy for T1/T2 breast cancer. Brachytherapy 2007;6:286e92.

37. Arthur DW, Winter K, Kuske RR, Bolton J, Rabinovitch R, White J, et al. A phase II trial of brachytherapy alone after lumpectomy for select breast cancer: tumor control and survival outcomes of RTOG 95-17. Int J Radiat Oncol Biol Phys 2008;72:467e73.

38. Ott OJ, Hildebrandt G, Pötter R, Hammer J, Lotter M, Resch A, et al. Accelerated partial breast irradiation with multi-catheter brachytherapy: local control, side effects and cosmetic outcome for 274 patients. Results of the GermanAustrian multi-centre trial. Radiother Oncol 2007;82:281e6.

39. Yoshida K, Nose T, Masuda N, Yamazaki H, Kotsuma T, Yoshida M, et al. Preliminary result of accelerated partial breast irradiation after breast-conserving surgery. Breast Cancer 2009;16:105e12.

40. Aristei C, Palumbo I, Cucciarelli F, Cavalli A, Tarducci R, Raymondi C, et al.

Partial breast irradiation with interstitial high-dose-rate brachytherapy in early breast cancer: results of a phase II prospective study. Eur J Surg Oncol 2009;35:144e50.

41. Lawenda BD, Taghian AG, Kachnic LA, Hamdi H, Smith BL, Gadd MA, et al.

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 2003;56:671e80.

42. Benitez PR, Keisch ME, Vicini F, Stolier A, Scroggins T, Walker A, et al.

Five-year results: the initial clinical trial of MammoSite balloon brachytherapy for partial breast irradiation in early-stage breast cancer. Am J Surg 2007;194:456e62.

43. Chao KK, Vicini FA, Wallace M, Mitchell C, Chen P, Ghilezan M, et al. Analysis of treatment efficacy, cosmesis, and toxicity using the MammoSite breast brachytherapy catheter to deliver accelerated partial-breast irradiation: the William Beaumont Hospital experience. Int J Radiat Oncol Biol Phys 2007;69:32e40.

44. Belkacémi Y, Chauvet MP, Giard S, Villette S, Lacornerie T, Bonodeau F, et al.

Partial breast irradiation as sole therapy for low risk breast carcinoma: early toxicity, cosmesis and quality of life results of a MammoSite brachytherapy phase II study. Radiother Oncol 2009;90:23e9.

45. Vicini F, Beitsch P, Quiet C, Gittleman M, Zannis V, Fine R, et al. Five-year analysis of treatment efficacy and cosmesis by the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial in patients treated with accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2011;79: 808e17.

46. Dickler A, Ivanov O, Francescatti D. Intraoperative radiation therapy in the treatment of early-stage breast cancer utilizing Xoft Axxent electronic brachytherapy. World J Surg Oncol 2009;7:24.

47. Ivanov O, Dickler A, Lum BY, Pellicane JV, Francescatti DS. Twelve-month follow-up results of a trial utilizing Axxent electronic brachytherapy to deliver intraoperative radiation therapy for early-stage breast cancer. Ann Surg Oncol 2011;18:453e8.

48. Dickler A, Patel RR, Wazer D. Breast brachytherapy devices. Expert Rev Med Devices 2009;6:325e33.

49. Strauss JB, Dickler A. Accelerated partial breast irradiation utilizing balloon brachytherapy techniques. Radiother Oncol 2009;91:157e65.

50. Veronesi U, Orecchia R, Luini A, Galimberti V, Zurrida S, Intra M, et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. Breast Cancer Res Treat 2010;124:141e51.

714

E.C. Moser, C. Vrieling / The Breast 21 (2012) 707e715

51. Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010;376:91e102.

52. Vaidya JS, Baum M, Tobias JS, Wenz F, Massarut S, Keshtgar M, et al. Longterm results of targeted intraoperative radiotherapy (Targit) boost during breast-conserving surgery. Int J Radiat Oncol Biol Phys 2011;81:1091e7.

53. Sautter-Bihl ML, Sedlmayer F, Budach W, Dunst J, Engenhart-Cabillic R, Fietkau R, et al. Intraoperative radiotherapy as accelerated partial breast irradiation for early breast cancer: beware of one-stop shops? Strahlenther Onkol 2010;186:651e7.

54. Anderson BO, Masetti R, Silverstein MJ. Oncoplastic approaches to partial mastectomy: an overview of volume-displacement techniques. Lancet Oncol 2005;6:145e57.

55. Njeh CF, Saunders MW, Langton CM. Accelerated partial breast irradiation using external beam conformal radiation therapy: a review. Crit Rev Oncol Hematol 2012;81:1e20.

56. Taghian AG, Alm El-Din M, Smith BL. Interim results of a phase I/II trial of 3Dconformal external beam accelerated partial breast irradiation in patients with early breast cancer. Int J Radiat Oncol Biol Phys 2008;72:S4.

57. Patel RR, Becker SJ, Das RK, Mackie TR. A dosimetric comparison of accelerated partial breast irradiation techniques: multicatheter interstitial brachytherapy, three-dimension conformal radiotherapy, and supine versus prone helical tomotherapy. Int J Radiat Oncol Biol Phys 2007;68:935e42.

58. Formenti SC, Gidea-Addeo D, Goldberg JD, Roses DF, Guth A, et al. Phase IeII trial of prone accelerated intensity modulated radiation therapy to the breast to optimally spare normal tissue. J Clin Oncol 2007;25:2236e42.

59. Vicini F, Winter K, Wong J, Pass H, Rabinovitch R, Chafe S, et al. Initial efficacy results of RTOG 0319: three-dimensional conformal radiation therapy (3DCRT) confined to the region of the lumpectomy cavity for stage I/II breast carcinoma. Int J Radiat Oncol Biol Phys 2010;77:1120e7.

60. Chen PY, Gustafson GS, Mitchell C, Wallace M, Hasan Y, Martinez AA, et al.

Three-year clinical experience utilizing 3D-conformal radiation therapy to deliver accelerated partial breast irradiation (APBI). Int J Radiat Oncol Biol Phys 2008;72:S3e4.

61. Lewin AA, Derhagopian R, Saigal K, Panoff JE, Abitbol A, Wieczorek DJ, et al.

Accelerated partial breast irradiation is safe and effective using intensitymodulated radiation therapy in selected early-stage breast cancer. Int J Radiat Oncol Biol Phys 2012;82:2104e10.

62. Reynders T, Tournel K, De Coninck P, Heymann S, Vinh-Hung V, Van Parijs H, et al. Dosimetric assessment of static and helical TomoTherapy in the clinical implementation of breast cancer treatments. Radiother Oncol 2009;93:71e9.

63. Prionas ND, McKenney SE, Stern RL, Boone JM. Kilovoltage rotational external beam radiotherapy on a breast computed tomography platform: a feasibility study. Int J Radiat Oncol Biol Phys 2012;84(2):533e9.

64. Kozak KR, Smith BL, Adams J, Kornmehl E, Katz A, Gadd M, et al. Accelerated partial-breast irradiation using proton beams: initial clinical experience. Int J Radiat Oncol Biol Phys 2006;66:691e8.

65. Keller B, Sankreacha R, Rakovitch E, O’brien P, Pignol JP. A permanent breast seed implant as partial breast radiation therapy for early-stage patient: a comparison of palladium-103 and iodine-125 isotopes based on radiation safety considerations. Int J Radiat Oncol Biol Phys 2005;62:358e65.

66. Jansen N, Deneufbourg JM, Nickers P. Adjuvant stereotactic permanent seed breast implant: a boost series in view of partial breast irradiation. Int J Radiat Oncol Biol Phys 2007;67:1052e8.

67. Afsharpour H, Reniers B, Landry G, Pignol JP, Keller BM, Verhaegen F, et al.

Consequences of dose heterogeneity on the biological efficiency of 103Pd permanent breast seed implants. Phys Med Biol 2012;57:809e23.

68. Wilson M, Korourian S, Boneti C, Adkins L, Badgwell B, Lee J, et al. Long-term results of excision followed by radiofrequency ablation (eRFA) as the sole local therapy for breast cancer. ASBrS; 2012. Abstract 136.

69. Smith BD, Arthur DW, Buchholz TA, Haffty BG, Hahn CA, Hardenbergh PH, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009;74:987e1001.

70. Polgár C, Van Limbergen E, Pötter R, Kovács G, Polo A, Lyczek J, et al.

GEC-ESTRO breast cancer working group. Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: recommendations of the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence. Radiother Oncol 2009;2010(94):264e73.

71. Ott OJ, Hildebrandt G, Pötter R, Hammer J, Hindemith M, Resch A, et al. Accelerated partial breast irradiation with interstitial implants: risk factors associated with increased local recurrence. Int J Radiat Oncol Biol Phys 2011;80:1458e63.

72. Park CC, Mitsumori M, Nixon A, Recht A, Connolly J, Gelman R, et al. Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol 2000;18:1668e75.

73. Abdulkarim BS, Cuartero J, Hanson J, Deschênes J, Lesniak D, Sabri S. Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy. J Clin Oncol 2011;29:2852e8.

74. Demirci S, Broadwater G, Marks LB, Clough R, Prosnitz LR. Breast conservation therapy: the influence of molecular subtype and margins. Int J Radiat Oncol Biol Phys 2012;83:814e20.

75. Hattangadi-Gluth JA, Wo JY, Nguyen PL, Abi Raad RF, Sreedhara M, Niemierko A, et al. Basal subtype of invasive breast cancer is associated with a higher risk of true recurrence after conventional breast-conserving therapy.

Int J Radiat Oncol Biol Phys 2012;82:1185e91.

76. Kreike B, Halfwerk H, Armstrong N, Bult P, Foekens JA, Veltkamp SC, et al.

Local recurrence after breast-conserving therapy in relation to gene expression patterns in a large series of patients. Clin Cancer Res 2009;15:4181e90.

77. Vicini FA, Antonucci JV, Wallace M, Gilbert S, Goldstein NS, Kestin L, et al.

Long-term efficacy and patterns of failure after accelerated partial breast irradiation: a molecular assay-based clonality evaluation. Int J Radiat Oncol Biol Phys 2007;68:341e6.

78. Niméus-Malmström E, Krogh M, Malmström P, Strand C, Fredriksson I, Karlsson P, et al. Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy. Breast Cancer Res 2008;10:R34.

79. Sanghani M, Truong PT, Raad RA, Niemierko A, Lesperance M, Olivotto IA, et al.

Validation of a web-based predictive nomogram for ipsilateral breast tumor recurrence after breast conserving therapy. J Clin Oncol 2010;28:718e22.

80. Werkhoven E, Hart G, Tinteren H, Elkhuizen P, Collette L, Poortmans P, et al.

Nomogram to predict ipsilateral breast relapse based on pathology review from the EORTC 22881-10882 boost versus no boost trial. Radiother Oncol 2011;100:101e7.

81. Patel RR, Christensen ME, Hodge CW, Adkison JB, Das RK. Clinical outcome analysis in “high-risk” versus “low-risk” patients eligible for national surgical adjuvant breast and bowel B-39/radiation therapy oncology group 0413 trial: five-year results. Int J Radiat Oncol Biol Phys 2008;70:970e3.

82. Shaitelman SF, Vicini FA, Beitsch P, Haffty B, Keisch M, Lyden M. Five-year outcome of patients classified using the American Society for Radiation Oncology consensus statement guidelines for the application of accelerated partial breast irradiation: an analysis of patients treated on the American Society of Breast Surgeons MammoSite Registry Trial. Cancer 2010;116:4677e85.

83. Wolmark N, Curran WJ, Vicini F, et al. NSABP protocol B-39. RTOG protocol 0413. A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer. Available from: http://www.rtog.org/members/protocols/0413.

84. Moon HJ, Kim MJ, Kwak JY, Kim EK. Probably benign breast lesions on ultrasonography: a retrospective review of ultrasonographic features and clinical factors affecting the BI-RADS categorization. Acta Radiol 2010;51:375e82.

85. Orel S. Who should have breast magnetic resonance imaging evaluation?

J Clin Oncol 2008;26:703e11.

86. Deurloo EE, Muller SH, Peterse JL, Besnard AP, Gilhuijs KG. Clinically and mammographically occult breast lesions on MR images: potential effect of computerized assessment on clinical reading. Radiology 2005;234:693e701.

87. Gutierrez RL, DeMartini WB, Silbergeld JJ, Eby PR, Peacock S, et al. High cancer yield and positive predictive value: outcomes at a center routinely using preoperative breast MRI for staging. AJR Am J Roentgenol 2011;196:W93e9.

88. Al-Hallaq HA, Mell LK, Bradley JA, Chen LF, Ali AN, Weichselbaum RR, et al.

Magnetic resonance imaging identifies multifocal and multicentric disease in breast cancer patients who are eligible for partial breast irradiation. Cancer 2008;113:2408e14.

89. Kühr M, Wolfgarten M, Stölzle M, Leutner C, Höller T, Schrading S, et al.

Potential impact of preoperative magnetic resonance imaging of the breast on patient selection for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2011;81:e541e546.

90. Landis DM, Luo W, Song J, Bellon JR, Punglia RS, Wong JS, et al. Variability among breast radiation oncologists in delineation of the postsurgical lumpectomy cavity. Int J Radiat Oncol Biol Phys 2007;67:1299e308.

91. Benda RK, Yasuda G, Sethi A, Gabram SG, Hinerman RW, Mendenhall NP. Breast boost: are we missing the target? Cancer 2003;97:905e9.

92. Dzhugashvili M, Tournay E, Pichenot C, Dunant A, Pessoa E, Khallel A, et al.

3D-conformal accelerated partial breast irradiation treatment planning: the value of surgical clips in the delineation of the lumpectomy cavity. Radiat Oncol 2009;4:70.

93. Weed DW, Yan D, Martinez AA, Vicini FA, Wilkinson TJ, Wong J. The validity of surgical clips as a radiographic surrogate for the lumpectomy cavity in imageguided accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2004;60:484e92.

94. Jobsen JJ, van der Palen J, Ong F. Effect of external boost volume in breastconserving therapy on local control with long-term follow-up. Int J Radiat Oncol Biol Phys 2008;71:115e22.

95. Vrieling C, Collette L, Fourquet A, Hoogenraad WJ, Horiot JH, Jager JJ, et al. The influence of patient, tumor and treatment factors on the cosmetic results after breast-conserving therapy in the EORTC “boost vs. no boost” trial. Radiother Oncol 2000;55:219e32.

96. Cochrane RA, Valasiadou P, Wilson AR, Al-Ghazal SK, Macmillan RD. Cosmesis and satisfaction after breast-conserving surgery correlates with percentage of breast volume excised. Br J Surg 2003;90:1505e9.

97. Bartelink H, Horiot JC, Poortmans P, Struikmans H, Van den Bogaert W, Barillot I, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345:1378e87.

98. Stroom J, Schlief A, Alderliesten T, Peterse H, Bartelink H, Gilhuijs K. Using histopathology breast cancer data to reduce clinical target volume margins at radiotherapy. Int J Radiat Oncol Biol Phys 2009;74:898e905.

E.C. Moser, C. Vrieling / The Breast 21 (2012) 707e715 99. van Loon J, Siedschlag C, Stroom J, Blauwgeers H, van Suylen RJ, Knegjens J, et al. Microscopic disease extension in three dimensions for non-small-cell lung cancer: development of a prediction model using pathology-validated positron emission tomography and computed tomography features. Int J Radiat Oncol Biol Phys 2012;82:448e56.

100. Rosenstein BS, Lymberis SC, Formenti SC. Biologic comparison of partial breast irradiation protocols. Int J Radiat Oncol Biol Phys 2004;60:1393e404.

101. Probst H, Griffiths S. Moving to a high-tech approach to the irradiation of early breast cancer: is it possible to balance efficacy, morbidity and resource use? Clin Oncol 2006;18:268e75.

102. Trakul N, Chang CN, Harris J, Chapman C, Rao A, Shen J, et al. Tumor volumeadapted dosing in stereotactic ablative radiotherapy of lung tumors. Int J Radiat Oncol Biol Phys 2012;84(1):231e7.

103. Greco C, Zelefsky MJ, Lovelock M, Fuks Z, Hunt M, Rosenzweig K, et al.

Predictors of local control after single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases. Int J Radiat Oncol Biol Phys 2011;79:1151e7.

104. Shah C, Wilkinson JB, Shaitelman S, Grills I, Wallace M, Mitchell C, et al.

Clinical outcomes using accelerated partial breast irradiation in patients with invasive lobular carcinoma. Int J Radiat Oncol Biol Phys 2011;81:e547e51.

105. Vicini FA, Chen P, Wallace M, Mitchell C, Hasan Y, Grills I, et al. Interim cosmetic results and toxicity using 3D conformal external beam radiotherapy to deliver accelerated partial breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 2007;69:1124e30.

106. Bentzen SM, Yarnold JR. Reports of unexpected late side effects of accelerated partial breast irradiationeradiobiological considerations. Int J Radiat Oncol Biol Phys 2010;77:969e73.

107. Jagsi R, Ben-David MA, Moran JM, Marsh RB, Griffith KA, Hayman JA, et al.

Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation.

Int J Radiat Oncol Biol Phys 2010;76:71e8.

108. Hepel JT, Tokita M, MacAusland SG, Evans SB, Hiatt JR, Price LL, et al. Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2009;75:1290e6.

109. Recht A, Ancukiewicz M, Alm El-Din MA, Lu XQ, Martin C, Berman SM, et al.

Lung dose-volume parameters and the risk of pneumonitis for patients treated with accelerated partial-breast irradiation using three-dimensional conformal radiotherapy. J Clin Oncol 2009;27:3887e93.

110. Moser EC, Noordijk EM, van Glabbeke M, Teodorovic I, de Wolf-Peeters C, Carde P, et al. Long-term efficacy of the CHVmP/BV regimen used for aggressive non-Hodgkin’s lymphoma in three randomised EORTC trials. Eur J Cancer 2004;40:474e80.

111. Dodwell DJ, Dyker K, Brown J, Hawkins K, Cohen D, Stead M, et al. A randomised study of whole-breast vs tumour-bed irradiation after local excision and axillary dissection for early breast cancer. Clin Oncol 2005;17:618e22.

112. Ribeiro GG, Magee B, Swindell R, Harris M, Banerjee SS. The Christie Hospital breast conservation trial: an update at 8 years from inception. Clin Oncol 1993;5:278e83.

113. Polgár C, Fodor J, Major T, Németh G, Lövey K, Orosz Z, et al. Breast-conserving treatment with partial or whole breast irradiation for low-risk invasive breast cancer e 5-year results of a randomized trial. Int J Radiat Oncol Biol Phys 2007;69:694e702.

114. Valachis A, Mauri D, Polyzos NP, Mavroudis D, Georgoulias V, Casazza G. Partial breast irradiation or whole breast radiotherapy for early breast cancer: a meta-analysis of randomized controlled trials. Breast J 2010;16:245e51.

115. Ontario Clinical Oncology Group, Canadian Institutes of Health Research, Canadian Breast Cancer Research Alliance. RAPID: randomized trial of accelerated partial breast irradiation. Available from: http://www.clinicaltrials.gov/ ct2/show/NCT00282035.

715

116. Strnad V, Polgár C; on behalf of the European Brachytherapy Breast Cancer GEC-ESTRO Working Group. Phase III multicenter trial. Interstitial brachytherapy alone versus external beam radiation therapy after breast conserving surgery for low risk invasive carcinoma and low risk duct carcinoma in-situ (DCIS) of the female breast. Available from: http://www.apbi.uni-erlangen.de.

117. Yarnold J, Coles C; on behalf of the IMPORT LOW Trial Management Group.

Intensity modulated and partial organ radiotherapy. Randomised trial testing intensity modulated and partial organ radiotherapy following breast conservation surgery for early breast cancer. Available from: http://www.clinicaltrials. gov/ct2/show/NCT00814567.

118. Orecchia R, Ciocca M, Tosi G, Franzetti S, Luini A, Gatti G, et al. Intraoperative electron beam radiotherapy (ELIOT) to the breast: a need for a quality assurance programme.

Breast 2005;14:541e6.

119. Armaroli L, Barbieri E, Bertoni F, Busutti L, Cardinali M, Cartei F, et al. Breast cancer with low risk of local recurrence: partial and accelerated radiation with three-dimensional conformal radiotherapy (3DCRT) vs. standard radiotherapy after conserving surgery (phase III study). Version 01.05 2007. Available from: http://groups.eortc.be/radio/res/irma/synopsis_trial_irma1.pdf.

120. Belkacemi Y, Lartigau E, Bourgier C. Standard of hypofractionated radiotherapy versus accelerated partial breast irradiation (APBI) for breast cancer (SHARE). Available from: http://www.clinicaltrials.gov/ct2/show/NCT01247233? term¼APBIþSHARE&rank¼1.

121. Orecchia R, Leonardi MC. IORT update: what are the limits of total dose and volume? Radiother Oncol 2012;103. SP-0097.

122. Mammosite: targeted radiation therapy. Available at: http://www.mammosite. com/physicians [accessed 15.08.12].

123. Vicini F, Arthur D, Wazer D, Chen P, Mitchell C, Wallace M, et al. Limitations of the American Society of Therapeutic Radiology and Oncology Consensus Panel guidelines on the use of accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2011;79:977e84.

124. Wilkinson JB, Reid RE, Shaitelman SF, Chen PY, Mitchell CK, Wallace MF, et al.

Outcomes of breast cancer patients with triple negative receptor status treated with accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2011;81:e159e64.

125. Shah C, Antonucci JV, Wilkinson JB, Wallace M, Ghilezan M, Chen P, et al.

Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast irradiation: results of a matched-pair analysis. Radiother Oncol 2011;100:210e4.

126. McHaffie DR, Patel RR, Adkison JB, Das RK, Geye HM, Cannon GM. Outcomes after accelerated partial breast irradiation in patients with ASTRO consensus statement cautionary features. Int J Radiat Oncol Biol Phys 2011;81:46e51.

127. Leonardi MC, Maisonneuve P, Mastropasqua MG, Morra A, Lazzari R, Rotmensz N, et al. How do the ASTRO consensus statement guidelines for the application of accelerated partial breast irradiation fit intraoperative radiotherapy? A retrospective analysis of patients treated at the European Institute of Oncology. Int J Radiat Oncol Biol Phys 2012;83:806e13.

128. Husain ZA, Mahmood U, Hanlon A, Neuner G, Buras R, Tkaczuk K, et al.

Accelerated partial breast irradiation via brachytherapy: a patterns-of-care analysis with ASTRO consensus statement groupings. Brachytherapy 2011;10:479e85.

129. Mannino M, Yarnold J. Accelerated partial breast irradiation trials: diversity in rationale and design. Radiother Oncol 2009;91:16e22.

130. Smith GL, Xu Y, Buchholz TA, Giordano SH, Smith BD. Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole-breast irradiation in older patients. In: 34th Annual San Antonio Breast Cancer Symposium (SABCS); 2011. Abstract S2-1.

131. Smith GL, Xu Y, Buchholz TA, Giordano SH, Jiang J, Shih YC, et al. Association between treatment with brachytherapy vs whole-breast irradiation and subsequent mastectomy, complications, and survival among older women with invasive breast cancer. JAMA 2012;307:1827e37.