The less than whole breast radiotherapy approach

The Breast 19 (2010) 180e187

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The Breast journal homepage: www.elsevier.com/brst

Original Article

The less than whole breast radiotherapy approach Margot Lehman a, *, Brigid Hickey b a b

Southern Zone Radiation Oncology, Princess Alexandra Hospital, Brisbane, Australia Southern Zone Radiation Oncology, Mater Centre, Brisbane, Australia

a b s t r a c t Keywords: Partial breast irradiation Accelerated partial breast irradiation Interstitial brachytherapy Intracavitary braachytherapy Intraoperative radiotherapy External beam radiotherapy Permanent seed implant

The addition of conventional whole breast irradiation (WBI) to breast conserving surgery (BCS) reduces the risk of early breast cancer recurrence and leads to a statistically and clinically significant improvement in overall survival. However, the long duration of conventional WBI regimens negatively impacts on quality of life. This has led investigators to evaluate an alternative approach of delivering radiation to a limited volume of tissue around the tumour cavity only (partial breast irradiation) and delivering a larger than standard dose of radiation with each treatment (accelerated partial breast irradiation, APBI). This approach may be achieved by a number of techniques: interstitial brachytherapy, intracavitary brachytherapy using the Mammosite device, intraoperative techniques using electrons or low-energy photons, external beam radiotherapy or permanent seed implant. This articles will review the rationale for the less that whole breast radiotherapy approach and describe the techniques by which it can be achieved and the results obtained to date. Finally, the 7 prospective randomised controlled trials of conventional WBI versus APBI which are open and currently recruiting patients will be discussed. Ó 2010 Elsevier Ltd. All rights reserved.

Historically, mastectomy was the recommended therapeutic option for all stages of breast cancer. However, with the publication of large randomised trials demonstrating equivalent survival for women with early stage disease (Stages I, II) treated with either breast conserving therapy (BCT) or mastectomy, breast conservation became the preferred management option for these patients.1e6 Conventional BCT consists of wide local excision of the tumour, achieving clear margins, followed by radiation therapy delivered to the whole breast with the aim of sterilizing remaining tumour cells. This practice is supported by data from detailed pathological examination of mastectomy specimens demonstrating a high frequency of multicentric residual tumour.7,8 The most recent Early Breast Cancer Trialists’ Collaborative Group overview has demonstrated a 19% absolute reduction in the 5-year risk of ipsilateral breast recurrence and a 5% absolute reduction in the 15-year risk of death from breast cancer with the addition of whole breast irradiation (WBI) to breast conserving surgery. Thus, the prevention of four local recurrences by WBI prevents one breast cancer related death at 15 years.9 Furthermore, when neither the volume of breast tissue excised nor the radiation fraction size is excessive, cosmetic results are satisfactory.10 Conventional radiotherapy schedules deliver 45e50 Gy to the whole breast over 4e5 weeks followed by a boost to the tumour bed of between 10 and 16 Gy over 1e2 weeks. This prolonged

treatment negatively impacts on quality of life11 and contributes to the higher mastectomy rates observed in women residing in areas remote from the nearest radiation facility.12 Consequently investigators have explored methods to reduce overall treatment time. Less than whole breast radiotherapy (also known as partial breast irradiation, PBI) refers to irradiation of a limited volume of breast tissue around the tumour bed. It may be achieved by any of the following techniques (1) (2) (3) (4)

Interstitial brachytherapy Intracavitary brachytherapy using the MammoSiteÒ device Intraoperative techniques using electrons or X-rays at 50 kV External beam radiotherapy (EBRT) using either three-dimensional conformal external beam radiotherapy (3D EBRT) or other methods (intensity modulated radiotherapy (IMRT), Tomotherapy or protons). (5) Permanent seed implant. These techniques deliver a larger than standard dose of radiation with each treatment, allowing the overall treatment time to be shortened. This is called accelerated partial breast irradiation (APBI). Rationale

* Corresponding author. E-mail address: [email protected] (M. Lehman). 0960-9776/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2010.03.005

The rationale for PBI is twofold. Firstly, most ipsilateral breast tumour recurrences occur in the same quadrant of the breast as the

M. Lehman, B. Hickey / The Breast 19 (2010) 180e187

original tumour. Spatial patterns of ipsilateral breast tumour recurrence reported in five randomised trials of breast conserving surgery with or without WBI demonstrated a 76e90% incidence of “same site” relapse, with the definition of “same site” encompassing the tumour bed, the surgical field, the surgical scar, the boost volume and the index breast quadrant.13e17 Furthermore, the distribution of cancer in the breast of a patient deemed suitable for breast conserving therapy using modern screening mammographic equipment may be different from the distribution seen in women presenting with clinically detectable lesions undergoing mastectomy. Recent studies examining primary and re-excision pathological specimens removed at the time of breast conserving surgery revealed residual tumour less than 10 and 15 mm from the primary tumour in 75e81% and 90% of specimens. If only cases with initial negative margins (as per NSABP criteria) were studied, residual disease was found <10 mm from the edge of the original tumour in >90% of cases.19 Secondly, WBI may not protect against the development of new primary cancers in the irradiated breast. In the Milan I trial which compared mastectomy with quadrantectomy and WBI, similar rates of other quadrant breast recurrence and contralateral breast cancers were reported.6 At 15 years, the Yale group report a 13% incidence of new cancers remote from the tumour bed compared with 10% incidence of contralateral cancer in 1152 patients undergoing BCT.18 If WBI prevented the development of a new primary cancer, the rate of such cancers in the treated breast should be lower than the incidence of cancer in the nonirradiated breast. The use of APBI has a number of potential advantages. Reducing overall treatment time is more convenient for patients and may increase the use of BCT. Reducing the volume treated may reduce normal tissue toxicity and may allow breast preservation should a recurrence occur elsewhere in the treated breast. Reducing the treatment time for a common malignancy may impact favourably on radiotherapy waiting times and treatment costs, important for countries with strained resources. However, the use of APBI has a number of potential disadvantages. The risk of local recurrence may be increased due to occult foci of cancer elsewhere in the breast not being treated. The higher radiation dose per fraction may increase late toxicity with adverse effects on cosmesis. At the present time, there are unanswered questions concerning the role of PBI. These include: (1) Which patients are best served by this approach? Given the limited volume of breast tissue irradiated, patients should only be considered if they have a low risk of clinically occult disease at a distance from the lumpectomy site. The clinical and pathological criteria which define this group are uncertain. (2) How is the target volume for PBI best defined? (3) What is the optimal technique of administration of PBI? (4) What is the optimal radiation dose/fractionation regimen? Radiobiological modelling (using an a/b of 4 for breast tissue and correction for cellular proliferation), reveals biological equivalent doses for a variety of APBI regimens lower than those for standard fractionation regimens of 60e66 Gy.20 (5) What are the long-term effects on local control, survival and toxicity? Currently, there is a paucity of Level 1 evidence concerning the efficacy of APBI. However, seven prospective randomised Phase III trials comparing WBI with APBI are currently underway. In the following sections the various APBI techniques employed in these trials are discussed and the results of Phase I/II trials presented.

181

APBI techniques and results Interstitial brachytherapy This technique involves inserting up to 10e20 catheters directly into the surgical cavity and surrounding tissue. Radioactive sources temporarily inserted into these catheters aim to irradiate the operative bed plus a 1e2 cm margin. Multicatheter interstitial brachytherapy was the first technique used in early studies of APBI. Unfortunately, local recurrence rates of between 6 and 37% were reported, reflecting poor patient selection, poor treatment technique and poor quality assurance procedures.21e24 The results of contemporary Phase II trials utilising stricter patient selection criteria and quality assurance procedures are presented in Table 1. These trials differ in their inclusion criteria but, in general, patients aged between 35 and 70 years with T1, T2 N0 or pN1 margin negative, invasive ductal carcinomas were included. High dose rate (HDR), low dose rate (LDR) or pulsed dose rate (PDR) brachytherapy techniques were used with different target volume definitions and different radiation dose/fractionation regimens. With follow-up ranging from 2.1 to 11 years, the incidence of ipsilateral local recurrence varies from 0 to 9% and excellent/good cosmesis is reported in between 56 and 100% of cases.25e38 Interstitial brachytherapy is an invasive technique that requires specialised equipment and a high level of expertise. It cannot be used for tumour cavities located near the axilla or in areas with limited breast tissue. There is a potential for dose inhomogeneity within the target leading to fat necrosis and subcutaneous toxicity39 but the technique provides good sparing of normal tissue.40 Intracavitary brachytherapy with MammoSiteÒ This device was developed in an attempt to simplify the brachytherapy procedure. It consists of an inflatable balloon attached to a double-lumen catheter. The balloon is inserted into the surgical cavity either at the time of primary surgery or at a later date using ultrasound guidance. The balloon is inflated so that the surrounding tissue is stretched around it and a high dose rate source (commonly 192Ir) is inserted through the catheter into the centre of the balloon delivering radiation to the rind of tissue surrounding the surgical cavity. The most commonly employed dose is 34 Gy in 10 fractions given twice daily with a minimum 6 h interfraction interval, prescribed 1 cm from the balloon surface.42e51 This achieves good sparing of normal tissues. Reported clinical outcomes with the use of the MammoSiteÒ device are presented in Table 2. Local recurrence rates are low (0e5.7%) with excellent/good cosmesis reported in 76e99% of cases, but follow-up is short.42e51 With increasing use of the MammoSiteÒ device, the following concerns and problems have been identified: (1) Adequacy of tumour coverage and potential for dose inhomogeneity. Placement of the source in the centre of the balloon assumes the tumour was located in the centre of the surgical cavity, which may not be the case. Surgical cavities vary in shape and non-conformity of the balloon to the cavity wall has been reported in 7e22% of cases.47,52 The technique is not suitable for large or irregular cavities. (2) Infection (4e12% incidence, particularly with peri-operative open cavity insertion)42,46e48,51 and a 20e52% incidence of seroma formation.42e44,48e50 (3) Worse cosmetic outcome with short balloon to skin distance. High rates of telangiectasia have been reported with balloon to skin distances of <7e15 mm.42,43,49

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Table 1 Results of contemporary multicatheter interstitial brachytherapy APBI trials. Institution/study HNIO, Budapest25,26

William Beaumont Hosp27,28

N 45

199

Orebro Medical Centre29 Tufts30

50 33

RTOG 95-1731

99

Ochsner Clinic32

51

GermaneAustria33

274

Wisconsin Univ34

273

Univ Kansas35

25

Osaka National Hosp36

45

Univ Perugia37

80

Mass Gen38

48

Inclusion criteria

Technique

RT scheme (TD Gy/no of fractions)

Target

Median F/UP (years)

IBTRa

Excellent/good cosmesis

IDC T1 pN0eN1mi G1e2 Margins neg EIC neg >40 years, IDC, T  3 cm, G1e3 Margins  2 mm Node neg EIC neg T1eT2 T1eT2 pN0eN1 Nonlobular Margins neg <3 cm Nonlobular 0e3 nodes pos T  4 cm pN0eN1 Margins neg >35 years T  3 cm pN0eN1mi Margins  2 mm ER pos EIC neg Low-risk þ high-risk features (<50, node pos, ER neg) 60 T  2 cm G1e2 pN0e1 Median age 44 (26e68) IDC/ILC T1seT2 Margin pos Median age 66 (49e84) IDC T  2.5 cm Node neg Margin neg 18 years T1N0 Margin neg EIC neg

HDR

30.3e36.4/7 (4 days)

LC þ 1e2 cm (clips)

11.1

8.9%

78%

LDR HDR

50/1 32/8e34/10 (4e5 days)

LC þ 1e2 cm

8.6

3%

99%

PDR HDR

50/0.83 (5 days) 34/10 (5 days)

LC þ 3 cm

7.2 7

6% 9.1%

56% 93%

LDR HDR

45/1 34/10 (5 days)

LC (clips) þ 1e2 cm

6.7

6.1%

NR

LDR HDR

45/1 32/8 (5 days)

Segmental mast þ 2e3 cm

6.25

2%

75%

PDR HDR

49.8 (83  0.6 Gy/1 h) (5 days) 36.4/7 (4 days)

LC þ 2 cm

4

2.2%

92%

HDR

32e34/8e10

LC ¼ 1.5e2 cm margin

4

3%

NR

LDR

20e25/1

3.9

0

100

HDR

36e42/6e7

LC þ 2 cm

2.6

4%

NR

HDR

32/8 (4 days)

LC þ 1e2 cm

2.5

0%

96%

LDR

50 Gy/1 55 Gy/1 60 Gy/1

1.9

0%

92%

LC ¼ local tumour cavity. a IBTR ¼ ipsilateral breast tumour recurrence.

(4) Uncertainty over the optimal time of insertion. Complete pathological information, which may contraindicate brachytherapy, may not be available at the time of intraoperative insertion. Post-operative insertion is invasive, requiring a second incision and the surgical cavity changes over time. (5) The cost of the device limits its availability in many countries. 3D conformal external beam radiotherapy (3D CRT) 3D EBCRT is advantageous because it is non-invasive and uses equipment commonly available in modern radiotherapy departments. 3D conformal approaches have been described using supine53,54 or prone55 set-up, simple or multi-field arrangements

and different forms of ionizing radiation (photons,54,55 photoneelectron mix,53 protons56). The appropriate clinical target volume is debatable but typically incorporates the surgical cavity with a 1e1.5 cm margin which is trimmed to spare skin and chest wall. An additional margin of 0.5e1.0 cm is added to account for respiratory motion and variation in set-up. Identifying the surgical cavity can be difficult leading to interobserver variability in target volume definition.57 The optimal dose fractionation regimen is yet to be determined. Compared with brachytherapy techniques, 3D CRT APBI offers greater dose homogeneity at the expense of higher dose to non-target tissues.41 The results achieved with 3D CRT APBI are presented in Table 3. With short follow-up, the rate of in-breast recurrence varies from 1 to 6%.58e61

M. Lehman, B. Hickey / The Breast 19 (2010) 180e187

183

Table 2 Results of MammoSiteÒ HDR brachytherapy APBI trials. Institution/study

N

FDA Trial42

43

Kiel-HNIO43

11

ASBS Registry Trial44

Rush Univ45 USA multicentric

1449

70 46

483

Univ South Carolina47

90

WBH48

80

European Multicentre49

28

Lille Univ50

25

Pittsburgh51

92

Inclusion criteria

RT scheme

Median F/UP (years)

IBTR

Excellent/good cosmesis

Telangiectasia

Complications

45 years Ductal T  2 cm Node neg Margin neg No EIC 60 Ductal T < 2 cm G1e2 Margins  5 mm No EIC >45 years Ductal T  2 cm N0 Margin neg No EIC “Early breast cancer” Lobular and DCIS allowed >45 Ductal T < 3 cm Margin neg DCIS, IDC T  3 cm 3 nodes pos >40 Stages 0eII Ductal, lobular or mixed, Margin  2 mm rec 3 pos nodes 60 years T  2 cm Ductal G1e2 Margin  5 mm EIC neg 60 Ductal T  2 cm Node neg Margins  5 mm >40 T < 3 cm pN0eN1mi Margins  2 mm EIC neg

34/10 (5 days)

5.4

O

83.3%a

39.5%

9.3% infection 32.6% seroma (symptomatic 12%)

34/10

1.7

0

67%b

26%b

43% seroma

34/10 (5 days)

3.1

2.15%

91%

NR

23.9% seroma

34/10

2.2

5.7%c

93%

NR

NR

34/10

2

1.2%

91%

17%

9% infection 14% sig subcutaneous toxicity

34/10

2

2.2%

90%

NR

4.4% major infection

34/10

1.8

2.5%

97%

NR

7.6% symptomatic seromas 11% infection

34/10

1.2

0

76%

18%

Seroma 40% 11.5% infection

34/10

1.1

0

84%

8%

52% seroma 8% severe infections

34/10

2

0

100%

10%

44% seroma 12% infection 4% rib fracture

a

In 36 patients with >5-year follow-up. Includes patients where MammoSite used as a boost. c The characteristics of the 4cases which developed in-breast failure: (1) Grade 3 IDC, node positive, ER negative (2) 8 mm Grade 2 IDC with EIC and closest margin of 1 mm (3) ILC (4) DCIS/LCIS. b

Intraoperative radiation therapy (IORT) using electrons or lowenergy X-rays at 50 kV (1) IORT using electrons After quadrantectomy, an electron applicator connected to a dedicated linear accelerator located in the operating room is placed over the surgical cavity. A single fraction of 21 Gy is delivered to the cavity and a margin of 1.5e3 cm of normal tissue using 3e10 Mev electrons. The largest reported series comes from Milan.62 An in-breast recurrence rate of 1% is reported at a mean follow-up of 2 years in a cohort of 590 patients with tumours <2.5 cm in diameter. (2) IORT using low-energy X-rays e intraoperative targeted radiotherapy (TARGIT) This technique utilizes low-energy X-rays of 50 kV. After lumpectomy, an appropriately sized applicator sphere is

placed in the surgical cavity and the breast tissue is sutured around it. 20 Gy in one fraction is prescribed to the applicators surface, which corresponds to 5e7 Gy at 1 cm from the applicator depending on the applicator size. The assumption that this dose is sufficient to sterilise microscopic residual disease has not yet been clinically validated. Treatment can last between 20 and 45 min. This technique was deemed feasible and safe by the investigators (no recurrences at a median follow-up of 2 years) in a pilot study of twenty-five patients in which TARGIT was used as a boost.63 Another publication of the TARGIT group shows a local relapse rate of 1.3% (4 out of 301 patients) after a median follow-up of 25 months (3e80 months) which means an actuarial local relapse rate of 2.6% after 5 years.64 Both intraoperative techniques rely on specialised equipment and a high level of technical expertise. The final

184

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Table 3 Clinical outcomes of APBI with 3D EBCRT. Study/institution

N

Inclusion criteria

RT schema

Median F/UP (years)

IBTR, %

Excellent/good cosmesis

William Beaumont59,60

96

34e38.5 Gy/10 fractions (5 days)

3

1

90%

Mass Gen61

99

32 Gy/8 fractions (4 days)

3

2

95%a

RTOG 031962

58

45 Ductal/lobular T  3 cm Margin  2 mm 3 nodes pos EIC neg Ductal pT1 N0 Margins  2 mm EIC/LVI neg T  3 cm 3 nodes pos Margin neg

38.5 Gy/10 fractions (5 days)

3.5

6

NR

a

Patient assessment.

pathological status of margins and lymph nodes is not available at the time of treatment delivery, thus radiotherapy may be given inappropriately to some patients. IORT with electrons is not suitable for tumours located near the skin or brachial plexus and TARGIT is not suitable for large or irregular tumour

cavities. In both techniques, dosimetry quality assurance may be difficult. Furthermore delivering radiation in a single large dose does not allow for the potentially beneficial radiobiological effects of reoxygenation and redistribution on enhancing radiosensitivity.20

Table 4 Prospective Phase III trials APBI. Trial

Trial design

N

Inclusion criteria

Control Arm

Experimental Arm

Activated

NSABP B-39/RTOG 041371

Equivalence

4300

WBI 50e50.4 Gy/25e28 fractions 10e16 Gy boost

Multicatheter bracytherapy/ MammoSite 34 Gy/10 fractions (5e10 days) Or 3D EBCRT 38.5 Gy/10 fractions (5e10 days)

2005 (accrual now closed to low-risk patients)

RAPID/Ontario Clinical Oncology Group72

Equivalence

2128

WBI 42.5 Gy/16 fractions/22 days (small breast) 50 Gy/25 fractions/35 days (large breasts) 10 Gy/4e5 fractions boost

3D EBCRT 38.5 Gy/10 fractions/5e8 days

2006

GEC-ESTRO73

Non-inferiority, non-irrelevant, 3% difference

1170

WBI 50e50.4 Gy/25e28 fractions  10 Gy boost

Interstitial brachytherapy 32 Gy/8 fractions HDR, 30.3 Gy/7 fractions HDR, 50 Gy PDR

2004

IMPORT LOW74

Non-inferiority

1935

WBI 40 Gy/15 fractions/21 days

3D EBCRT Arm1: 40 Gy/15 fractions to primary tumour region þ 36 Gy/15 fractions to low-risk region Arm 2: 40 Gy/15 fractions to primary tumour region

2006

ELIOT75

Equivalence

824

WBI 50 Gy/25 fractions  10 Gy boost

Intraoperative electrons 21 Gy/1 fractions electrons up to 9 Mev

Dec 2000

TARGIT76

Equivalence

2232

WBI As per institutional guidelines

Low-energy X-rays 50 kV 20 Gy/1 fraction

March 2000

IRMA77

Non-inferiority

18 years Stage 0, I or II (T < 3 cm) DCIS or invasive adenocarcinoma 3 nodes pos Lumpectomy Margin neg PBI judged to be technically deliverable 40 years DCIS or invasive carcinoma T < 3 cm Margin neg Node neg Not BRCA 1/BRCA 2 Age  40 Stages 0eII Ductal/lobular carcinoma DCIS T  3 cm pN0epNmi Margin  2 mm 50 Invasive adenocarcinoma (not lobular) T  3 cm Margin 2 mm Node neg 48 Invasive carcinoma T  2.5 cm pN0 Quadrantectomy 45 T1, smallT2 N0-1 Ductal 49 pT1e2 (<3 cm) Invasive Ca pN0eN1 Margins  2 mm

WBI

3D EBCRT 38.5 Gy/10 fractions/5 days

2007

M. Lehman, B. Hickey / The Breast 19 (2010) 180e187

Permanent breast seed implant A technique using 103Pd permanent seed implants has been described.65 Studies evaluating the practicality, efficacy and toxicity of this approach are underway. Phase III trials Currently, the results of three phase III trials evaluating APBI are available and a meta-analysis of these results has been performed recently. A Hungarian Phase III trial compared WBI with APBI using HDR implants (69%) or electron beams (31%) in 258 women with margin negative, histological Grade 2 or less, pT1 cN0, pN0 or pN1mi breast cancers. This study was stopped when <50% of the planned sample size had been accrued due to a competing trial. At a median followup of 66 months, the 5-year actuarial rate of local recurrence was 4.7% in the PBI arm and 3.4% in the WBI arm (p ¼ 0.50). The 5-year actuarial local recurrence rate was 22.2% in women aged less than 41 compared with 3% in older women (p ¼ 0.016).66,67 In the Christie Hospital trial68 713 women were randomised to receive WBI (40 Gy/15 fractions) or APBI to the affected quadrant (40e42.5 Gy/8 fractions over 10 days, using 10 MeV electrons with an average field size of 8  6 cm). With a median follow-up of 65 months, the risk of ipsilateral breast recurrence was 19.6% and 11% in the APBI and WBI arms respectively (p ¼ 0.0008). Patients were eligible if they had a clinically palpable mass 4 cm, mammographic evaluation was not mandatory and specimen margins were not evaluated microscopically. Both invasive ductal and invasive lobular histologies were included. A more select patient group was included in the Yorkshire Breast Cancer Group Trial (YBCG).69 174 women were randomised to receive 40 Gy/15 fractions (with a 15 Gy tumour bed boost) WBI or 55 Gy/20 fractions to the tumour bed (defined clinically) using a variety of techniques. With a median follow-up of 8 years, the risk of in-breast recurrence was 12% and 4% in the PBI and WBI arms respectively (p ¼ 0.07). A meta-analysis of these three randomised Phase III trials was presented at ASCO in 2009.70 PBI was associated with an increased risk for both local (pooled odds ratio (OR 2.150); 95% CI 1.396e3.312; p ¼ 0.001) and regional recurrence (pooled OR 3.430; 95% CI 2.058e5.715; p < 0.001). This did not translate into a survival difference (OR 0.912; 95% CI 0.674e1.234; p ¼ 0.550). It is important to remember that the two studies which contributed 77% of patients to this meta-analysis (YBCG, Christie) used patient selection criteria, target volume definition and radiotherapy techniques which would not be considered standard of care today. Seven prospective randomised Phase III trials comparing APBI with WBI are currently recruiting patients. The studies are presented in detail in Table 4.71e77 These trials differ in a number of respects: (1) Patient selection criteria. Only one study (NSABP B-39/RTOG 041371) allows patients as young as eighteen to be enrolled. One study (ELIOT75) mandates quadrantectomy; the remaining studies require lumpectomy with negative margins. All studies exclude tumours 3 cm in diameter. Nodal involvement (up to pN1) is allowed in four trials (NSABP, GEC-ESTRO73, TARGIT76, IRMA77). Two trials limit inclusion to ductal carcinomas only (IMPORT LOW74, TARGIT). The NSABP trial closed accrual to patients with low-risk features in 2007. Accrual is now limited to patients with one or more high risk features (age < 50, 1e3 nodes positive, ER negative). (2) Radiotherapy techniques. The experimental arm is 3D EBCRT in the RAPID and IRMA trials. HDR or PDR brachytherapy is the

185

experimental arm in the GEC-ESTRO Trial. HDR, MammoSiteÒ, or 3D EBCRT is allowed in the NSABP trial. The ELIOT and TARGIT trials employ intraoperative therapy with either electrons or low-energy photons respectively. In all trials, clinical outcomes will be influenced by technical expertise and quality assurance procedures. (3) Radiation dose fractionation regimens. Dose rate and dose distribution vary between the different regimens. The control arm is 42.5 Gy/16 fractions (RAPID72) and 50e50.4 Gy/25e28 fractions in the remaining trials.71,73,75e77 The IMPORT LOW74 is a three-arm trial, using fixed multisegmented tangential beams to deliver 40 Gy/15 fractions to the whole breast (control arm), partial breast or partial breast plus a lower dose (36 Gy/ 15) to the remainder of the breast (experimental arms). Mature results of these studies should provide information regarding the long-term efficacy and safety of APBI approaches. However, it is likely that the optimal treatment technique will remain uncertain as a direct comparison of the techniques is not part of any of the current trials. Finally it is hoped that knowledge of patterns of relapse will provide guidance on the appropriate patient selection criteria for APBI. However, it is likely that mature results will not be available for at least another 10 years. In response to the increasing use of APBI off clinical trial the American Society for Radiation Oncology (ASTRO) has published a consensus statement regarding appropriate patient selection criteria for APBI used off trial.78 However, the authors “strongly endorsed enrolment of all eligible patients considering APBI into prospective clinical trials to address many of the unanswered questions in APBI”. Conclusion The evolution of the management of early breast cancer has occurred over many years. The former gold standard of mastectomy was only abandoned when numerous randomised controlled clinical trials demonstrated the efficacy and safety of breast conserving therapy. In women with early breast cancer, WBI post breast conserving surgery safely reduces the risk of ipsilateral breast recurrence and results in a small but statistically and clinically significant survival benefit. While APBI has a number of theoretical advantages, these should not be allowed to overshadow the uncertainties regarding its optimal use. Until the mature results of Phase III studies become available, APBI should be considered an experimental therapy. Conflict of Interest Statement None declared. References 1. Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham D, Cronin W, et al. Re-analysis and results after 12 years of follow-up in a randomised clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995;333(22):1456e61. 2. Veronesi U, Salvadori B, Luini A, Greco M, Saccozzi R, del Vecchio M, et al. Breast conservation is a safe method in patients with a small cancer of the breast. Long-term results of three randomised trial on 1973 patients. Eur J Cancer 1995;31(10):1574e9. 3. Early Breast Cancer Trialists’ Collaborative Group. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomised trials. New Engl J Med 1995;333(22):1444e55. 4. Van Dongen JA, Voogd AC, Fentiman IS, Legrand C, Sylvester RJ, Tong D, et al. Long-term results of a randomised trial comparing breast-conserving therapy with mastectomy: European organisation for research and treatment of cancer 10801 trial. J Natl Cancer Inst 2000;92(14):1143e50. 5. Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomised trial comparing total mastectomy,

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