Efficacy and safety of intraoperative radiotherapy in breast cancer: A systematic review

Cancer Letters 313 (2011) 15–25

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Efficacy and safety of intraoperative radiotherapy in breast cancer: A systematic review A. Ruano-Ravina a,b,c,⇑, P. Cantero-Muñoz a, A. Eraso Urién d a

Galician Agency for Health Technology Assessment, Galician Department of Health, Spain Department of Preventive Medicine and Public Health, School of Medicine, University of Santiago de Compostela, Spain c CIBER de Epidemiología y Salud Pública, CIBERESP, Spain d Radiation Oncology Service, Catalan Institute of Oncology (ICO), Spain b

a r t i c l e

i n f o

Article history: Received 5 May 2011 Received in revised form 4 August 2011 Accepted 22 August 2011

Keywords: Intraoperative radiotherapy Breast neoplasms Systematic review

a b s t r a c t The objective of this study is to assess the efficacy and safety of intraoperative radiotherapy (IORT) for early breast cancer through a systematic review. Fifteen studies met the inclusion criteria. Most studies assessed the combined treatment with IORT (10–24 Gy) and external beam radiotherapy (EBRT) (45–50 Gy) on early stage breast cancer (T0–2). Local control was over 95% for 1 and 4 years of follow-up and the 5-year overall survival was 99%. The TARGIT-A study found a similar survival comparing IORT with standard treatment. The incidence of acute and chronic complications was scarce. IORT is well tolerated by patients and acute and late toxicities are low. There are no differences in survival for IORT treated patients versus standard treatment. Ó 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Breast cancer is the most frequent malignant neoplasm in women, especially after the age of 50, ranking first in developed countries [1,2]. It is the fifth cause of death worldwide and the third in Europe, after lung and colorectal cancer, causing 0.5 million deaths every year [1,3]. From the 1990s breast cancer mortality has been declining, mainly in women younger than 50, as a result of advances in screening and treatment [4,5]. Its prognosis depends principally on tumor size, growth rate and whether there is metastasis at the regional and distal lymph nodes [6]. For localized tumors, 5-year survival reaches 98% but if there is metastasis to the lymph nodes or other organs 5-year survival decreases to 75% and 14%, respectively [4].

⇑ Corresponding author at: School of Medicine, Department of Preventive Medicine and Public Health, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain. Tel.: +34 881 812267; fax: +34 881 812433. E-mail address: [email protected] (A. Ruano-Ravina). 0304-3835/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2011.08.020

There are several possibilities to treat breast cancer. The choice depends on the clinical and pathological characteristics of the tumor, stage, presence of hormone receptors, positive result for certain biological factors such as Her2, comorbidity, age and patient’s hormonal status [7]. Conventional treatment for stages I and II breast cancer consists of breast conservative treatment with lumpectomy, surgical axillary staging and whole breast radiotherapy [7–10]. Postoperative adjuvant radiotherapy (EBRT) is generally delivered 6 weeks after surgery in fractionated daily doses during 5–6 weeks (45–50 Gy fractionated in 1.8–2.0 Gy per day) and also as a boost over the tumor bed. The EORTC 22881–10882 trial showed that an additional boost of 16 Gy reduces a 4% the risk of local recurrence in 10.8 years [11]. When there are positive lymph nodes after mastectomy, radiotherapy reduces a 17% the 5-year risk of local recurrence [7]. Delivering the conservative treatment the local recurrence rate is over 20% and varies depending on the surgical technique used. Approximately 85% of local recurrences appear in tissue adjacent to the primary tumor after traditional surgery within 5 years of diagnosis. In stage I, the 10-year recurrence rate is 10–30%

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and in stage II the 5-year recurrence rate is 40–50%. When postoperative radiotherapy is delivered the local recurrence rate is a 10% lower [12,13]. To reduce the probability of recurrences should be a treatment goal, since a breast cancer death is avoided through the prevention of four local recurrences (with a 15 year follow-up) [14]. Radiotherapy techniques have become more sophisticated. Improvements aim at delivering higher effective radiation doses without increasing side effects. To achieve this goal sensitive structures are protected or displaced at the moment of applying radiation. One of these techniques is intraoperative radiotherapy (IORT): a single radiation dose delivered under direct, visual and palpable inspection of the tumor. It thus improves local recurrence and diminishes toxicity since there is less irradiation of healthy tissue. Also, there is no lapse of time between surgery and radiotherapy. The objective of this study is to assess the efficacy and safety of IORT in the treatment of early breast cancer regarding local recurrences and overall survival through a systematic review of scientific literature. 2. Bibliographic search Scientific literature published between January 2000 and October 2009 was systematically reviewed. The main databases specialised in systematic reviews were used: the NHS Centre for Reviews and Dissemination, including Health Technology Assessment (HTA), Database of Abstracts of Reviews of Effectiveness (DARE) and NHS EED (Economic Evaluation Database), and the Cochrane Plus Library. General databases such as Medline, Embase, ISI Web of Knowledge (Institute for Scientific Information), IME (Spanish Medical Index) and Tripdatabase were also searched. In order to locate current research projects USA database Clinicaltrials.gov and other international registers, such as Current Controlled Trials (CCT), were reviewed. To complete this search, other national scientific societies and organizations’ databases were reviewed manually in order to add more information of interest. For each database specific search strategies were applied using unique combinations and different variations of free terms. The main search terms were ‘intraoperative’, ‘radiotherapy’ and ‘breast neoplasm’. After the search was completed the TARGIT-A study was published in May 2010. Its results have been included in the systematic review [15]. 3. Inclusion and exclusion criteria for the retrieved papers The retrieved studies were read and those meeting the inclusion criteria were selected. The criteria were as follows: (1) regarding the study’s design, systematic reviews, metaanalysis, clinical trials, cohort and case-control studies, cross-sectional studies and case series were included; (2) sample size: a minimum of 30 patients treated with IORT; (3) treatment type: patients who received intraoperative electron-beam radiotherapy (IOERT) or X-ray radiotherapy (IORT); (4) outcomes measurement: studies which assessed mortality, morbidity, quality of life, 3 or 5 year survival,

disease’s local control and short and long term toxicity; (5) patient type: adults diagnosed with breast cancer in any stage; (6) patient inclusion period: studies in which the delivery of IORT for most patients was after 2000; (7) follow-up period: studies with a median follow-up of at least 3 months; (8) language: only publications in English, French, Italian, Spanish and Portuguese were included. Two reviewers critically read the selected studies in an independent and blind manner, deciding the work’s final inclusion by consensus. Finally, the most relevant data were rigorous and uniformly extracted into specifically designed evidence tables. In order to assess the quality of the included studies, a specifically adapted scale was used. The scale, had been previously employed in studies regarding the use of IORT for pancreatic cancer [16,17]. It was used independently and blindly by both reviewers and is shown in Table 1. Differences over one point were not allowed and if arisen were resolved by consensus.

4. Description of research performed on intraoperative radiotherapy for early breast cancer The bibliographic search yielded 287 references. After the abstracts were reviewed, 29 studies were read in their entirety of which 14 and the TARGIT-A study met the established selection criteria (Fig. 1). Three systematic reviews [18–20] and a randomized clinical trial were included; the remaining studies were case series. Median follow-up period was equal or over 36 months in five studies and between 9 and 48 months in the remaining studies. Sample size was over 200 patients in most of studies and reached 500 patients in four studies [15,21,22,26]. The studies’ country of origin was mainly European: five originated from Italy [21,24,26,27,30], four from Germany [19,25,28,29] and two were multicenter studies [15,22]. Three studies originated from Australia and two were collaborations between different countries [15,23].

5. Effectiveness and efficacy The results obtained by the systematic reviews show that adding IORT to conventional treatment improves the disease’s local control but not survival, concluding its use to be experimental [18–20]. The included studies in those systematic reviews contain publications dated between 1965 and 2008, do not show results for all the studies or patients characteristics and often include low quality studies. They assess the use of several types of IORT in the treatment of stages I–II breast cancer, although one study includes non-gynecological solid tumors among which there are cases of breast cancer [20]. Cosmetic results are considered good or excellent in over 80% of cases and the most frequent side effects are seroma, wound healing problems and fibrosis. The results of the primary studies are shown according to the type of radiotherapy delivered, an IORT boost followed by a conventional regimen of EBRT or a single IORT dose. Table 2 reflects the main characteristics of the studies included.

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A. Ruano-Ravina et al. / Cancer Letters 313 (2011) 15–25 Table 1 Quality criteria for the included studies. Criteria

Points

Sample size

<100 patients P100 patients

0 1

Comparative study

Case-series Comparison group

0 2

Follow-up

Mean or median follow-up <24 months Mean or median follow-up P24 months

0 1.5

Toxicity

Short and long-term IORT toxicity is not assessed Short and long-term IORT toxicity is assessed Short and long-term IORT toxicity is assessed with commonly used accepted scales (EORTC/RTOG or LENT SOMA)

0 0.5 1

Patients’ characteristics

Included patients are heterogeneous (ample age range, ample TNM range, tumor size) Included patients are homogeneous (age range relatively narrow, limited TNM and limited tumor size)

0 2

IORT dose

Delivered IORT dose for patients with similar characteristics is heterogeneous Delivered IORT dose for patients with similar characteristics is homogenous

0 1

External radiotherapy (EBRT)

Heterogeneous dose Homogeneous dose

0 1

Time lapse between IORT and EBRT

P30 days

0

<30 days

0.5

Total

TARGIT-A is a multicenter randomized clinical trial and it included 2323 patients, randomly selected to receive either IORT or EBRT [15]. Its follow-up period was 4 years, although the median follow-up has not been provided. The delivered IORT dose was 20 Gy. Patients suffered from primary, unifocal invasive ductal carcinoma and were over 45 years of age. After the follow-up period the difference between local recurrences in the two groups was 0.25% (not significant). Three studies combined 10–20 Gy IORT doses with 37–54 Gy total EBRT doses [22,23,27]. In the Ivaldi et al. series 204 premenopausal women with T1–2N0–1 invasive carcinoma received a single IORT dose (12 Gy) and a 37.05 Gy EBRT dose. After a 9-month follow-up period the incidence of distant recurrences was 2.5% and there were no local recurrence [27]. In the Vaidya et al. multicenter study 20 Gy IORT doses are combined with 45–50 Gy EBRT doses. Seventy-eight percent of patients suffered from T1 tumors and 21% from T2 tumors. After a followup period of 30–72 months there were four local recurrences (1.3%) and 10 deaths, five due to metastasis. Fiveyear disease-free survival was 97% and 7-year disease free survival was 83% [23]. Finally, the ISIORT-Europe group assessed over 1000 patients suffering from T0–3N0–x breast cancer treated with a 9.7 Gy IORT median dose and a 50–54 Gy EBRT dose. Local tumor control was 99.4% for a 52.3-month follow-up period. Seven-year overall survival was 90.9% [22]. On the other hand, studies which use only or mainly IORT delivered a higher single dose radiation, 17–24 Gy, on invasive tumors sized 1–2.5 cm [24,26,30]. In the Mussari et al. series 42.5% of patients received 24 Gy, another 42.5% received 22 Gy and the remaining patients 20 Gy. The follow-up period was 48 months; there were two contralateral recurrences, no local recurrences and a distant recurrence in the 37th month [30].

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Intra et al. treated 95.7% of patients with 21 Gy. They observed three local recurrences on the 13th, 17th and 19th months of follow-up [24]. Veronesi et al. obtained similar results on 590 patients. Ninety-six percent of patients received a single 21 Gy dose and the remaining patients a combination of IORT (10–15 Gy) and EBRT (44–40 Gy). Three patients treated with IORT 21 Gy doses developed local recurrences in 28–36 months [26]. In the Kraus-Tiefembacher’s et al. study 42% of patients with invasive tumors P3 cm received a 20 Gy IORT dose and 48% received a combination of IORT (20 Gy) and EBRT (46 Gy). In 10 months, only one patient from the combination group developed an invasive local recurrence [25]. Finally, in the Petit et al. case series, 678 patients underwent a modified mastectomy (Nipple Sparing Mastectomy) which preserved the nipple areola complex (NAC). Eightyone percent of patients with T1–3 invasive tumors received a 16 Gy boost after surgery. The remaining 18% presented an in situ disease treated with 16 Gy in 1–2 fractionated daily doses. The local recurrence rate was close to an annual 1% and 75% of cases appeared in the primary tumor bed. Five-year overall survival was 99.6%, NAC was preserved in 54 patients and in 19 months there were no local recurrences [21]. 6. Safety Toxicity of the included studies was assessed through the use of different scales such as the RTOG/EORTC scale and the CTC criteria (version 2.0) for acute toxicity and the LENT-SOMA scale for late toxicity. No study used the CTC 3.0 or 4.0 versions published in 2003 and 2009 respectively. The main safety results are shown in Table 3. Acute and late toxicity associated with the delivery of an IORT boost followed by EBRT was assessed by a reduced number of studies [27,28,31]. In the Ivaldi et al. study 98%

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Fig. 1. Bibliographic search results.

of patients received a 12 Gy boost as well as adjuvant treatment. Median time lapse between the delivery of IORT and EBRT was 22 days. During this time nine patients developed fat necrosis in the radiated quadrant. Acute toxicity assessed through the RTOG/EORTC scale showed the highest incidence of skin side effects on completion of EBRT. The late toxicity determined (LENT-SOMA) in 108 patients revealed a case of grade IV cutaneous toxicity. Fifty-one percent of patients developed grades I–II toxicity and 49% did not show any side effect [27]. Wenz et al. assessed the effect of the time lapse on late toxicity between the delivery of a 20 Gy IORT dose and a 50 Gy EBRT (fractionated) dose on T1–2N0–2 tumor patients (mean time lapse was 36 days). Sixty-three percent of patients did not develop relevant changes and less than 10% showed chronic skin toxicity. The highest toxicity degrees are linked to significantly shorter IORT–EBRT time lapses (29 versus 39 days) [28]. Finally, Joseph et al. delivered a 5 Gy IORT boost alongside 45 Gy of EBRT to 35

patients with time intervals between each radiation ranging from 37 to 221 days. No patient developed acutemoderate side effects (grades III–IV) and most showed mild symptoms (grades 0–II dermatitis and pain) [31]. Mussari et al., Intra et al. and Veronesi et al. assessed the viability of delivering a single IORT dose at the early stage of the disease and its long-term effects [24,26,30]. The Mussari et al. series showed a progressive development of fibrosis during the first months after surgery reaching its peak in 24 months. In 3 years, one patient radiated with 24 Gy developed fibrosis III with skin retractions and 14 patients developed fibrosis II, of which seven had received 24 Gy. Changes in pigmentation (III), telangiectasia (III), edema and pain in the radiated area were also observed [30]. Intra et al. found three severe side effects after a 27-month follow-up period (one case of moderate fibrosis in the radiated area, one case of acute fibrosis and one case of moderate retractions). This study was the only that assessed cardiac toxicity, founding no cardiac complications related to IORT

Table 2 Evidence tables of included studies. Author, location, recruitment period

Study type, mean follow-up (months)

Patients and diagnoses

Treatment

Results

Score

Vaidya et al. [15]

Randomized clinical trial

N = 2.232

LR (4 years):

7.5

Multicentric study (2000–2010)

Follow-up: not specified, results shown after 4 years of follow-up

Status:

– IORT: 20 Gy with or without EBRT as shown below – EBRT: 40–56 Gy with or without a boost of 10–16 Gy

IORT group EBRT group T1: 33% T1: 36% T2: 52% T2: 49% T3: 15% T3: 15% Device: Intrabeam (X rays)

1.2% (IORT) 0.95% (EBRT)

Case series Follow-up: 19 (1–60 months)

N = 579 Status: T1–3 (81%), in situ (18%) – Device: ELIOT (e)

– IORT: 16 Gy (81.7%) – EBRT: 32 Gy (12.8%)

– LR: 0.9% at 1 year – DR: 1.5% at 1 year – OS: 99.6% at 5 years

3.5

Sedlmayer et al. [22] (Austria, Italy, Germany) (1998–2005)

Case series Follow-up: 52.3

N = 1.131 – Status: T0–3N0–x: T0 (5), T1 (695), T2 (295), T3 (7), N0 (611), N1 (343), N2 (32), N3 (7), Nx (9) – Device: unknown (e)

– IORT: 9.7 Gy (5–17 Gy) (100%) – EBRT: 50–54 Gy (100%)

– LR: 0.6% at 4.3 years – DR: 5.4% at 4.3 years

3.5

– Time interval IORT–EBRT: 6.6 weeks

– DFS: 88% at 7 years – OS: 90.9% at 7 years

Vaidya et al. [23] Multicentric (UK, Italy, Germany, Australia, USA) (1998–2005)

Case-series Follow-up: 3–80

N = 301 Status: T1 (78%); T2 (21%); N pos. (87); N neg. (205); unknown (10) – Device: Intrabeam (X rays)

– IORT: 18–20 Gy (100%) – EBRT: 45–50 Gy (100%)

– LR: 1.3% at 0.8–6.4 years – DR: 1.6% at 0.8–6.4 years

4.5

– OS: 99.6% at 2 years – DFS: 97.4% at 5 years

Ivaldi et al. [27] Italy (2004–2007)

Case-series Follow-up: 8.9 (0.8–32.4)

N = 204 – Status: T1–2N0–1 0 (4); I (94); IIA (73); IIB (18); IIIA (11); IIIC (4) – Device: Novac7, Linac

– IORT 12 Gy (100%) – EBRT: 37.05 Gy (100%) – Time interval IORT–EBRT: 22 days

– LR: 0% at 0.75 years – DR: 2.5% at 0.75 years

6.5

Wenz et al. [28]

Case-series

N = 59

– IORT: 20 Gy (100%)

Assesses adverse effects (Table 3)

6.5

Germany (2002–2004)

Follow-up: 36

Status: T1–2N0–2 – Device: Intrabeam (X rays)

– EBRT: 46–50 Gy (100%) – Time interval IORT–EBRT: 36 days

Kraus-Tiefenbacher et al. [29]

Case-series

N = 73

– IORT: 20 Gy (100%)

Assesses adverse effects (Table 3)

4.5

Germany (2002–2003)

Follow-up: 25 (18–44)

– Status: T1–2; N0–3 pN0 (50); pN1 (18); pN2 (3); pN3 (2) – Mean size: 15 mm

– EBRT: 46 Gy (100%) – Device: Intrabeam (X rays)

Joseph et al. [31] Australia (2001–2003)

Case-series Follow-up: 8.9 Conflict of interest

N = 35 – Size: 10 mm (1–30) N0 (25); N1 (6); Nx (5)

– IORT: 5 Gy (100%) – EBRT: 45 Gy (100%) – Time interval IORT–EBRT: 93 days

– LR: 0%

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Petit et al. [21] Italy (2002–2007)

(continued on next page) 19

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Table 2 (continued) Author, location, recruitment period

Study type, mean follow-up (months)

Kraus-Tiefenbacher et al. [25] Germany (2002–2003)

Case-series Follow-up: 18

Patients and diagnoses

Treatment

Results

Score

– IORT: 20 Gy (42%) – IORT: 20 Gy + EBRT 46 Gy (58%)

– LR: 1.8% at 0.8 years – DR: 3.5%

2

– IORT: 17 Gy (2.5%); 19 Gy (1.6%); 21 Gy (95.7%) – EBRT: 0 Gy

– Ipsilateral recurrence: 0.3% (17 months) – Contralateral recurrence: 0.5% (13–19 months)

5.5

– IORT: 21 Gy (96.1%) – IORT: 10 Gy + EBRT 44 Gy (2.7%)

– LR: 0.5% at 2 years – Ipsilateral recurrence: 0.5% at 2 years

4.5

– IORT: 15 Gy + EBRT 40 Gy (1.2%)

– Contralateral recurrence: 0.8% at 2 years – DR: 2.2% – OS: 99.8% at 2 years

– IORT: 20 Gy (15%); 22 Gy (42.5%); 24 Gy (42.5%) – EBRT: 0 Gy

– LR: 0% at 4 years

– Device: Intrabeam (X rays) N = 57 – Status: T1 (42); T2 (14); Tmic (1) N+ (13); N (44)

– Time interval IORT–EBRT: 3– 8 weeks

Retrospective case-series

N = 355 (251 ELIOT trial)

Italy (1999–2003)

Follow-up: 27.3

– Status: T1; T2 (62.5 cm)

Veronesi et al. [26] Italy (1999–2003)

Case-series Follow-up: 24 (4–57)

– Device: ELIOT (Novac7) N = 590 – Size: 65 mm (26); 5–10 mm (144); 10–15 mm (216); 15–20 mm (130);>20 (62); N1 (19); N pos. (68); N neg. (11) – Device: Novac7, Linac

Mussari et al. [30]

Case-series

N = 47

Italy (2000–2002)

Follow-up: 48 (36–63)

– Status: T1N0M0 – Size: <1 cm (31); 1–2 cm (16); N pos. (<3) (7) – Device: Elektra precise model (e)

– Contrateral recurrence: 4.2% at 4 years – DR: 2.1% at 4 years

e: electrons; LC: local control; LR: local recurrence; DR: distant recurrence; OS: overall survival; DFS: disease-free survival; IORT: intraoperative radiotherapy; EBRT: external beam radiotherapy.

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– Device: Intrabeam (X rays) Intra et al. [24]

Table 3 Safety results for the included studies. Author, year

Treatment

Toxicity

Mild complications (grades 0–I) (%)

Moderate complications (grades II– III) (%)

Serious complications (grade IV) (%)

Vaidya et al.

– IORT: 20 Gy with or without EBRT as shown below – EBRT: 40–56 Gy with or without a boost of 10–16 Gy

Any complication:

Not specified

Grade 3 (RTOG):

– IORT: None

– IORT: 17.6%

– IORT: 0.5%

– EBRT: None

– EBRT: 15.5%

– EBRT: 2.1%

N = 2.232

Ivaldi, 2008

IORT: 12 Gy + EBRT: 37 Gy (100%)

N = 204

Time interval: 22 days

 Skin: 40.2 (0); 52.3 (I)

 Skin: 6.8(II); 0.7 (III)

– Liponecrosis: 4.4  Pain: 49 (0); 40.8 (I)  Edema: 72.2 (0); 22.2 (I)  Fibrosis: 34.3 (0); 46.3 (I)  Telang.: 88 (0); 7.4 (I)  Lymphedema: 94.5 (0); 4.6 (I)  Retracction/atrophy: 63.9 (0); 28.7 (I)  Ulceration: 98.1 (0)

     

Wenz, 2008 N = 48

IORT: 20 Gy + EBRT: 46–50 Gy Time interval: 36 days

Late (LENT-SOMA) 6–12 months

     

Kraus-Tiefenbacher, 2006 N = 73

IORT: 20 Gy + EBRT: 46 Gy

Late (CTC/EORTC) (skin) 6 months

 Edema: 1.4

 Localized fibrosis: 19 (II); 1.4 (III)

 Mastitis: 2.7

 Whole breast fibrosis: 1.4 (II); 2.7 (III)

(LENT-SOMA) (fibrosis) 12 months

 Hyperpigmentation: 2.7

IORT: 20 Gy (15%); 22 Gy (42.5%); 24 Gy (42.5%) No EBRT

Late (RTOG/EORTC)

 Pain: 2 (I)

 Fibrosis: 30 (II); 2 (III)

6–36 months

 Infection: 8.5 (I)  Edema: 2 (I)

 Pigmentation changes: 4 (III)  Telang.: 2 (III)  Necrosis: 2 (II)

IORT: 17 Gy (2.5%); 19 Gy (1.6%); 21 Gy (95.7%) No EBRT

Late

IORT 20 Gy (24p)

Acute (CTC/EORTC)

Mussari, 2006 N = 47

Intra, 2005 N = 355 Kraus-Tiefenbacher, 2005 N = 57

Veronesi, 2005

Not indicated

IORT 20 Gy + EBRT 46 Gy (33p) Time interval: 3–8 weeks IORT: 21 Gy (574p)

Fibrosis: 26 (I) Telang: 6 (I) Edema: 9 (I) Retraction: 13 (I) Hyperpigmentation: 8 (I) Pain:13 (I)

Pain: 10.2 (II) Edema: 5.6 (II) Fibrosis: 18.5 (II); 0.9 (III) Telang.: 4.6 (II) Lymphedema: 0.9 (II) Retraction/atrophy: 7.4 (II)

 Necrosis: 0.5

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Acute (RTOG/ EORTC) 1 month Late (LENT-SOMA) 6–12 months N = 108p

 Fibrosis: 19 (II); 4 (III)  Edema: 2 (II)  Pain: 8 (II); 2 (III)

 Erithema: 4 (I)  Localized fibrosis: 8 (I)  Whole breast fibrosis: 0 (I)

 Fibrosis: 0.3 (II); 0.3 (III)

6–19 months

 Skin retraction: 0.3 (II)  Eritema II: 1.7 (IORT + EBRT)

Late (LENT-SOMA) 18 months

 Healing delay: 3.5 (IORT); 1.7 (IORT + EBRT)  Edema: 3.5 (IORT + EBRT)  Erithema I: 5.2 (IORT + EBRT)  Seroma: 1.7 (IORT); 3.5 (IORT + EBRT)

Acute (RTOG/

 Fibrosis: 3 (I)

 Fibrosis: 0.2 (II)

 Fibrosis II: 3.5 (IORT + EBRT)  Eritema II: 1.7 (IORT + EBRT)

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[24]. In the Veronesi et al. study, 6% of patients suffered from severe side effects, again mainly from moderate fibrosis and fat necrosis [26]. Kraus-Tiefenbacher et al. observed that the majority of side effects were found in patients radiated with IORT (20 Gy) and EBRT (46 Gy). One patient developed wound healing problems, two hematoma and one erythema while two patients who had received exclusively IORT (20 Gy) suffered healing problems. During the follow-up period some patients treated with EBRT developed erythema I–II (n = 4), fibrosis II (n = 2) and seroma (n = 3). Only one patient who had received IORT presented side effects [25]. The TARGIT-A [15] study showed little differences in toxicity between the two groups included. In the group treated with IORT grades III–IV toxicity was 0.5% increasing to 2.1% for the group who received external radiation. This was the only statistically significant result between the two groups.

 Dermatitis: 37 (II)  Pain: 37 (II)  Others: 2.8 (III) Dermatitis:82 (I) Pain: 80 (I) Breast infection: 17 (I) Armpit infection: 14 (I) Hematoma/seroma: 17 (I) Breast infection: 14 (I) Armpit infection: 2.8 (I)

7. Quality of the included studies

Late (RTOG/EORTC) 1 year (n = 11)

       IORT: 5 Gy + EBRT: 45 Gy Time interval: 93 days Joseph, 2004 N = 35

Acute (CTC) 1 month (n = 27)

 Fibrosis: 3.0 (II); 0.2 (III) Late (RTOG/EORTC) 6–36 months

 Hematoma: 0.3 (I)  Infection: 0.3 (I)  Skin retraction: 0.3 (I)

 Liponecrosis: 2.5 (I) EORTC) 1–6 months IORT (10–15 Gy) + EBRT (44–40 Gy) (16p) N = 590

Mild complications (grades 0–I) (%) Toxicity Treatment Author, year

Table 3 (continued)

Moderate complications (grades II– III) (%)

Serious complications (grade IV) (%)

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Following the application of the quality scale, the Kraus-Tiefenbacher study obtained the lowest score, two points [25], and TARGIT-A the highest, 7.5 points [15], followed by the Ivaldi and Wenz studies, both with 6.5 points [27,28]. Median score was 4.5 and four studies obtained a lower score [21,22,25,31]. 8. General comments on the assessed studies The results of this systematic review indicate that the use of IORT for the treatment of breast cancer is non-inferior to conventional treatment regarding local control. The higher dose homogeneity, the exclusion of non-affected structures from the radiation area and the avoidance of delay between surgery and radiotherapy place IORT as a promising alternative in the treatment for non-advanced breast cancer. Moreover, the recent publication of the TARGIT-A study has strengthened this review’s results due to its robust methodology and large sample size. Nevertheless, the TARGIT-A’s recurrence rate is only based on a median follow-up of 24 months and 11 events [15]. Survival data are only included in half of the studies [21–23,26] showing rates of over 98% in 2–5 years when using IORT. These results are between 10% and 18% higher than those from international and European registries [32,33]. Despite of these results we only can conclude that, with the available evidence, survival in patients treated with IORT is similar to those who received the standard treatment. The observed differences could be greatly attributable to the low quality of the studies, and also to the differences in the follow-up periods considered. These results are similar to those observed in the study of Clarke et al., which showed no survival advantage with any kind of radiotherapy in early breast cancer patients [14]. Early stage primary disease local control was over 95% in 1 [21,25,27] and 2 [26] years associated to the combination of a single IORT dose (12–20 Gy) and fractioned EBRT regimen (32–46 Gy). Similar results were obtained for a 4-year follow up period delivering 10–20 Gy of IORT and

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45–50 Gy of EBRT [22,23,30]. However, the Cuncins-Hearn review indicates that conventional treatment produces a 10-year local control a 20% higher than that produced by IORT, although definitive conclusions cannot be drawn given the low quality of the available evidence [18]. We have observed a great heterogeneity regarding different technical aspects: type of device, energy source (X-ray or electrons), IORT dose, whether EBRT is delivered postoperatively or not and the lapse of time between both (IORT–EBRT). This limits the possibility of comparisons between the included studies. Patients hormonal or hormone receptor data were detailed by few studies [15,21–23,28,30,31], three of which included women over 45 years of age with positive receptors in 80–100% of cases [24,25,30] while in another study close to 80% of patients were over 50 [25]. We expected to find better results in these studies. Nevertheless, the studies that included mainly premenopausal patients obtained similar results regarding local control (4-year 95%). This may be due to the differences on the percentage of positive receptors with age or to a better response to adjuvant treatment. It is very difficult to separate the effects of IORT from those of the hormonal treatment in premenopausal women [21,22,27]. Regarding tumor size and TNM stage there was heterogeneity among the different studies. The majority of patients had unifocal invasive tumor smaller than 2–3 cm in size [21,24–26,29–31]. None of the studies assessed stage T4 tumors and T3 tumors were evaluated by only two studies [21,22]. It seems that the diseases’ early stage benefits the most regarding local control with IORT. However, studies with no restrictions regarding tumor type, stage, state of hormonal receptors and number of affected lymphatic nodes showed a similar local recurrence and distant metastasis incidence (<1.3% and 1–5% in 4 years respectively), although in both studies over 95% of recurrences belonged to T1–2 tumors [22,23]. Most of the studies included evaluated the use of IORT as part of combined treatment with EBRT (45–50 Gy), although the use of higher IORT doses (21–24 Gy) was also assessed as sole radiation therapy for non-advanced stages of the disease on patients with low risk and tumors below 2.5 cm in size [24,30]. It was observed that the studies which do not include the delivery of EBRT show a slightly lower local control in 4 years. With regards to safety, the most frequent local side effects produced by external radiation of the whole breast include pain, coloration of the skin in the treated area, tiredness and discomfort. In the long term appear skin retraction and underarm edema in the case of irradiated axilla and, less frequently, heart damage, rib osteitis, brachial plexopathy and risk of secondary malignancies. Late toxicity compromises the benefits of postoperative radiotherapy for patients with early stage breast cancer [34]. With IORT the radiated volume is significantly reduced in an attempt to reduce the resulting adverse effects [7,35–38]. With IORT, the incidence of acute overall complications does not reach 10% [25,26]. These are in most cases mildmoderate effects (grades I–II) such as fibrosis, fat necrosis, edema, erythema and wound healing problems. There were few severe complications, less than 1%. There was one case of severe necrosis (grade IV) and two of skin

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reactions and fibrosis (grade III) [26,27]. The incidence rate of acute side effects is associated with the use of the highest IORT doses (21 Gy) with no EBRT, although these results originate from a small number of studies [25,26]. One study comparing the combined treatment of IORT (20 Gy) + EBRT (46 Gy) with IORT (20 Gy) showed a 4% lower incidence of acute side effects for IORT only [25]. In the long term, only one case of an acute ulcer (grade IV) was experienced with the delivery of 12 Gy IORT + 37 Gy EBRT [27]. Most described side effects are mild and do not require hospital stay, they are mainly skin reactions: hyperpigmentation, erythema and fibrosis [27,29]. The most frequent moderate complications (grade III) are fibrosis, skin pigmentation changes, pain and telangiectasia, with an incidence under 4% [24–28,30]. The use of IORT as the only radiotherapy treatment reveals that the most severe complications (fibrosis, pigmentation changes, grade III telangiectasia) are associated with the highest radiation doses, close to 24 Gy [28,39]. Moderate fibrosis is the most frequent adverse effect with an incidence close to 30% for 24 Gy IORT doses, decreasing over 25% when the dose is reduced to 20–21 Gy [26,30]. These results seem to be confirmed by the Intra et al. study, which shows a higher incidence rate directly attributable to 21 Gy IORT doses [24]. When delivering IORT doses over 21 Gy, hematoma, pain and edema appear in 2% of patients. There is no incidence of grade IV severe complications but incidence of grade III fat necrosis is under 3%, present mainly in women over 70 years of age with a high percentage of fat tissue in the breast. The development of fibrosis is progressive during the first 6 months of treatment, is especially evident after 6 months and reaches its peak in 24 months [26,30,39]. When comparing the mammographic results of treatment with 22–24 Gy IORT doses with those of conventional treatment patients who receive IORT show a higher number of structural distortions and edema. These effects are more evident within 12 months with the addition of necrosis and calcifications. In 24 months, conventional radiotherapy results show minimal tissue alterations and no cases of edema while IORT results do not improve [40]. Time lapse between IORT and EBRT delivery was 22– 93 days [27,28,31]. Despite the fact that some authors do not find a link between the length of this time lapse, local failure and acute or late adverse effects [22,25], it was observed that patients who develop the highest grades of toxicity were those who had experienced shorter time lapses between the two types of radiation, always shorter than 30 days [27,28].

9. Review limitations A possible limitation of this review is the use of different acute toxicity (RTOG/EORTC and the CTC criteria) and late toxicity (SOMA-LENT and RTOG/EORTC) scales [24–31]. The studies included in this review have used the most upto-date versions of the scales available at the time, with the exception of CTC adverse effects scale. Version 2.0 has been used by three studies while a more detailed version 3.0 was available. This could be due to the fact that when

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those studies began version 3.0 was not available and changing to a new version would difficult the comparison of the results. CTC 4.0 version, published in 2009, includes specific categories for the assessment of breast alterations and registers over 30 side effects on skin and subcutaneous tissue [41]. The variability in the selection of the assessment criteria and the differences shown by the different scales pose a problem when comparing the results. Regarding late toxicity a good correlation between the RTOG/EORTC and SOMA-LENT [42] scales has been observed. Since most studies used the RTOG/EORTC scale we do not consider this fact as a limitation. Nevertheless, there is other drawback related with the methods for the assessment of IORT late toxicity. The included studies do not use any type of survival analysis considering time to event (Kaplan Meier or actuarial), and only perform a description on the incidence of the adverse effects observed. Differences in follow-up time also difficult the comparison. With regards to the quality of the assessed studies, mean scores obtained applying our own scale did not surpass five points. The reasons were the small sample size of some studies, the fact that some studies did not include a comparison group, the lack of toxicity assessments, the fact that toxicity was not assessed using standard scales and the non-homogenous inclusion of patients. It is necessary to highlight that this scale has been developed to score certain characteristics in the studies but not their design exclusively. The lack of discordances between both reviewers regarding the use of the scale indicates its easiness of use and the reliability of the results. 10. Concluding remarks The available evidence on the efficacy and safety of IORT for the treatment of early stage breast cancer is of low quality and mainly comes from case studies. In the treatment of early stage tumors (T1–2N0), adding IORT to conventional treatment with surgery and EBRT seem to be associated with a lower incidence of local recurrences. It is also considered a safe technique as most acute complications were mild-moderate and the incidence of severe chronic complications was very low (<2%). The most frequent side effects were skin-related: fibrosis, fat necrosis, edema, erythema and wound healing problems. Currently, it is not possible to ascertain whether IORT can be delivered in combination with or in substitution of EBRT, as most studies assess its use associated with conventional surgery treatment and EBRT. It is necessary to undertake comparative studies analyzing defined patient subgroups for which IORT could be very beneficial. Note: an extended version of this document (157 pages) in Spanish is available free of charge in the website for the Galician Agency for Health Technology Assessment (avalia-t). Contributions All authors participated in the design, writing and final approval of the manuscript.

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