Chapter 9 Radiotherapy A New Approach to Risk- Adapted Selective Radiotherapy

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1 Chapter 9 Radiotherapy A New Approach to Risk- Adapted Selective Radiotherapy Csaba Polgár 9.1 Introduction During the last forty years, breast-conserving surgery (BCS) followed by whole breast irradiation (WBI), with or without an additional dose to the tumour bed, has become the standard of care for the treatment of early-stage (St. 0-I-II) breast carcinoma (Bartelink et al. 2007; Fisher et al. 2002a; Veronesi et al. 2002). Several randomized clinical trials have proved that WBI following BCS decreases the risk of recurrence in the ipsilateral breast by a factor of 3 to 4 for both invasive (Clark et al. 1992, 1996; Fisher et al. 1985, 1995; Ford et al. 2006; Forrest et al. 1996; Liljegren et al. 1994, 1999; Renton et al. 1996; Veronesi et al. 1993, 2001) (Table 9.1) and in situ carcinomas (Bijker et al. 2006; Emdin et al. 2006; Fisher et al. 1993, 1999, 2001; Houghton et al. 2003; Julien et al. 2000) (Table 9.2). Although individual trials failed to demonstrate a survival benefit from radiotherapy (RT), the Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis proved that the prevention of four local recurrences (LRs) by radiotherapy in the first 5 years would prevent about one breast cancer death over the next 15 years (Early Breast Cancer Trialists Collaborative Group (EBCTCG) 2005). With the advent of breast screening, the incidence of breast carcinomas with more favourable prognostic characteristics (including in situ, microinvasive and invasive tumours measuring up to 15 mm) has increased significantly. This change in the prognostic profile of newly diagnosed breast cancers has opened up new horizons for clinical research seeking individual risk-adapted protocols of breast cancer RT. Several groups have investigated the efficacy of accelerated (partial or whole) breast irradiation (APBI and AWBI), which have become new treatment C. Polgár ( ) Department of Radiotherapy, National Institute of Oncology, Ráth Gy. u. 7-9, 1122 Budapest, Hungary Tel.: Fax: polgar@oncol.hu Z. Kahán, T. Tot (eds.), Breast Cancer, a Heterogeneous Disease Entity, DOI / _9, Springer Science+Business Media B.V

2 212 C. Polgár Table 9.1 Clinical trials evaluating the effects of radiotherapy on local recurrence and overall survival in unselected patients with early invasive breast carcinoma after breast-conserving surgery Study Study period NSABP-B-06 (Fisher et al. 1985, 1995) OCOG (Clark et al. 1992, 1996) Milan III (Veronesi et al. 1993, 2001) Uppsala-Örebro (Liljegren et al. 1994, 1999) St. George s London (Ford et al. 2006; Renton et al. 1996) Scottish (Forrest et al. 1996) Year of first publication Patient n Patient selection criteria Median FU (years) LR (%) OS (%) BCS alone BCS + RT BCS alone BCS + RT ,450 T1-2 ( 4 cm) N T1-2 ( 4 cm) N0, free margins T1-2 ( 2.5 cm) N0-1, free margins T1 ( 2 cm) N0, free margins T1-2 ( 5 cm) N T1-2 ( 4 cm) N NR NR FU follow-up time, LR rate of local recurrence, OS overall survival, BCS breast-conserving surgery, RT radiotherapy, NSABP National Surgical Adjuvant Breast and Bowel Project, OCOG Ontario Clinical Oncology Group, NR not reported

3 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy 213 Table 9.2 Clinical trials evaluating the effect of radiotherapy on local recurrence in patients with DCIS after breast-conserving surgery Study Study period Year of first Patient Median FU LR (%) publication n (years) BCS alone BCS+RT BCS+TAM BCS+RT+TAM NSABP-B-17 (Fisher et al , 2001) NSABP-B-24 (Fisher et al , , 2001) EORTC (Bijker et al , ; Julien et al. 2000) UKCCCR (Houghton et al , ) SweDCIS (Emdin et al. 2006) , DCIS ductal carcinoma in situ, FU follow-up time, LR rate of local recurrence, BCS breast-conserving surgery, RT radiotherapy, TAM tamoxifen, NSABP National Surgical Adjuvant Breast and Bowel Project, EORTC European Organization for Research and Treatment of Cancer, UKCCCR United Kingdom Coordinating Committee on Cancer Research

4 214 C. Polgár options in the radiotherapy of breast cancer (Antonucci et al. 2009; Arthur et al. 2008; Benitez et al. 2007; Beriwal et al. 2008; Chen et al. 2010; Dickler et al. 2009; Dodwell et al. 2005; Fentiman et al. 1991, 1996, 2004; Formenti 2005; Hopwood et al. 2010; Hui et al. 2004; Johansson et al. 2009; Kaufman et al. 2007; Keisch et al. 2003; King et al. 2000; Kuske et al. 2006; Leonard et al. 2010; Livi et al. 2010; Magee et al. 1996; Niehoff et al. 2006; Orecchia et al. 2009; Ott et al. 2007; Owen et al. 2006; Perera et al. 1997, 2003; Pignol et al. 2006; Polgár et al. 1999, 2002, 2004, 2005, 2007, 2008, 2009, 2010a, b; Polgár and Major 2009; Póti et al. 2004; Ribeiro et al. 1995; Samuel et al. 1999; Scanderbeg et al. 2009; Smith et al. 2009; Strnad et al. 2004, 2010; Taghian et al. 2006; The START Trialists Group 2008a, b; Vaidya et al. 2010; Vicini et al. 1997, 2007a, b, 2008, 2010a, b, c; Vicini and Arthur 2005; Wazer et al. 2001; Whelan et al. 2010; Yarnold et al. 2005; Yarnold and Haviland 2010). Others have attempted to identify subgroups of patients for whom radiotherapy after BCS could be safely omitted (Fisher et al. 2002a, 2007; Fyles et al. 2004; Holli et al. 2001; Hughes et al. 2004; Lim et al. 2006; Malmström et al. 2003; Pötter et al. 2007; Schnitt et al. 1996; Winzer et al. 2004). This chapter reviews the results of such studies, focusing on risk-adapted radiotherapy after BCS for patients with ductal carcinoma in situ (DCIS) and small ( 15 mm) invasive breast carcinomas. 9.2 Accelerated Partial Breast Irradiation (APBI) Partial Breast Irradiation (PBI) is to restrict the irradiation to the region around the excised cancer most probably affected by cancerous growth. After excision in the localized, low-risk cases, the robust experience gained indicates that irradiation of the cancer-bearing region alone ensures local control equivalent to that achieved with WBI. PBI may be performed by conventional or accelerated fractionation. APBI is an attractive treatment approach that shortens the 5- to 7-week course of conventional postoperative radiotherapy to 4 5 days. The acceleration resulting from the delivery of higher than conventional radiotherapy doses during a relatively short treatment period eliminates some of the disadvantages of the extended treatment period, especially for elderly patients, women who work, and those who live at a significant distance from the radiotherapy facility. The rationale for APBI is that the majority of LRs occur in close proximity to the tumour bed (Polgár et al. 2005; Vicini and Arthur 2005). Fewer than 20% of the LRs appear elsewhere in the breast, and the absolute number of such failures is very low (e.g. far less than 1% per year and similar to the rate of new contralateral tumours) (Veronesi et al. 2002). In addition, some elsewhere failures are likely to be new primary breast cancers that arise after the radiotherapy and hence would not have been prevented by WBI. In the past twenty years, therefore, APBI involving the use of interstitial implants has been intensively evaluated in phase I-II studies as a possible alternative to conventional WBI (Polgár et al. 2005; Vicini and Arthur 2005).

5 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy Early APBI Trials In the 1980s and early 1990s, several European and American centres pioneered the use of different APBI regimens for unselected patients (Dodwell et al. 2005; Fentiman et al. 1991, 1996, 2004; Kaufman et al. 2007; Magee et al. 1996; Perera et al. 1997, 2003; Póti et al. 2004; Ribeiro et al. 1995). In fact, the results of these early studies were poor, with high LR rates (Table 9.3). The high rates of local failure reflected inadequate patient selection, suboptimum treatment techniques and the lack of appropriate quality assurance (QA) procedures (Polgár and Major 2009; Polgár et al. 2009; Vicini and Arthur 2005) Contemporary Phase II APBI Trials Involving Brachytherapy Techniques The controversial results of the earlier studies led several groups to create APBI trial protocols incorporating more strict patient selection criteria and systematic QA procedures. As a result, the outcomes of subsequent studies were much improved (Table 9.4) (Antonucci et al. 2009; Arthur et al. 2008; Benitez et al. 2007; Johansson et al. 2009; Keisch et al. 2003; King et al. 2000; Kuske et al. 2006; Niehoff et al. 2006; Ott et al. 2007; Polgár et al. 2004, 2007, 2008, 2009, 2010a; Polgár and Major 2009; Samuel et al. 1999; Strnad et al. 2004, 2010; Vicini et al. 2007a) Oschner Clinic Experience The first evaluation in the USA of the feasibility of APBI using multicatheter brachytherapy (BT) was that by Kuske et al. (King et al. 2000; Kuske et al. 2006) at the Oschner Clinic in New Orleans. Between 1992 and 1993, 50 patients were treated with either 45 Gy low-dose-rate (LDR) or 32 Gy high-dose-rate (HDR) BT, given in 8 fractions of 4 Gy. All patients had tumours measuring <4 cm with negative margins. Patients with negative or up to 3 positive axillary nodes were eligible. Wide-volume implants were used to encompass the excision cavity with 2 cm margins in all directions. At a median follow-up of 75 months, only 1 breast recurrence (2%) was observed. The authors compared the outcome of their patients with a matched control group of 94 patients who met the eligibility criteria for APBI, but who were treated with conventional WBI during the same period. The two groups were similar as concerns LR rates, cosmetic results and grade 3 side-effects William Beaumont Hospital (WBH) Experience The findings of one of the largest trials in which multicatheter BT was applied to deliver APBI were reported by the WBH group from Royal Oak, Michigan

6 216 C. Polgár Table 9.3 Early clinical studies with 5 years of follow-up, evaluating the efficacy of accelerated partial breast irradiation (APBI) after breast-conserving surgery in unselected patients Study Study period Year of first publication Guy s Hosp. I (Fentiman et al. 1991, 1996) Christie Hosp. (Magee et al. 1996; Ribeiro et al. 1995) Uzsoki Hosp. (Póti et al. 2004) London Regional Cancer Center (Perera et al. 1997, 2003) Tufts University (Kaufman et al. 2007) Guy s Hosp. II (Fentiman et al. 2004) Cookridge Hosp. (Dodwell et al. 2005) Patient n Patient selection criteria T1-2 N0-1, margins: 56% pos., ILC, EIC and LVI: allowed T1-2 ( 4 cm) Nx a, margins: 10% pos., 10% unknown, ILC, DCIS, EIC and LVI: allowed T1-2 N0-1 (Nx: 80%), margins: 100% unknown, ILC, DCIS, EIC and LVI: allowed T1-2 ( 4.5 cm) N0-1, margins: free (31% close), EIC and LVI: allowed T1-2N0-1; margins: free (45% close); EIC: allowed T1-2 ( 4 cm) N0-1, >40 years, margins: 43% pos., ILC, EIC and LVI: allowed T1-2 ( 4.5 cm) N0-1, margins: grossly free, ILC, EIC and LVI: allowed Technique of PBI Median FU (years) LR (%) PBI WBI LDR BT ELE MDR BT HDR BT HDR BT MDR BT EBI b PBI partial breast irradiation, FU follow-up time, LR rate of local recurrence, WBI whole breast irradiation, LDR low-dose rate, BT brachytherapy, ELE electrons, MDR medium-dose rate, HDR high-dose rate, EBI external beam irradation, ILC invasive lobular carcinoma, EIC extensive intraductal component, LVI lympho-vascular invasion, DCIS ductal carcinoma in situ a Axillary staging was omitted b A variety of external beam techniques were used, including a direct cobalt or caesium beam, electrons or megavoltage tangential photon beams

7 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy 217 Table 9.4 Contemporary clinical studies with 5 years follow-up, evaluating the efficacy of APBI for selected patients Study Study period William Beaumont Hospital a (Antonucci et al. 2009; Vicini et al. 2007a) Budapest Phase II a (Polgár et al. 2004, 2008, 2009, 2010a; Polgár and Major 2009) Ninewells Hosp. (Samuel et al. 1999) Ochsner Clinic a (King et al. 2000) Budapest Phase III (Polgár et al. 2007, 2008, 2009; Polgár and Major 2009) FDA MammoSite Registry Trial (Benitez et al. 2007; Keisch et al. 2003) Year of first publication Patient n Patient selection criteria T1-2 (<3 cm) N0-1 (1 3 pos. nodes); margins 2 mm; age >40 years; ILC, DCIS and EIC: excluded T1 ( 2 cm) N0-1mi; clear margins; HG 1 2; ILC, DCIS and EIC: excluded NS T1-2 ( 3.5 cm) N0-1 (1 pos. node); ILC and EIC excluded Tis-1-2 (<4 cm) N0-1 (1 3 pos. nodes); free margins; ILC, EIC and LVI: allowed T1 ( 2 cm) N0-1mi; margins 2 mm; HG 1 2; age >40 years; ILC, DCIS and EIC: excluded T1 ( 2 cm) N0; free margins; age 45 years; ILC, DCIS and EIC: excluded Technique of PBI Median FU (years) LR (%) PBI WBI LDR/HDR BT HDR BT LDR BT LDR BT HDR BT/ELE MammoSite BT 5.2 0

8 218 C. Polgár Table 9.4 (continued) Study Study period German-Austrian Phase II (Strnad et al. 2004, 2010; Ott et al. 2007) Year of first publication Patient n Patient selection criteria T1-2 (<3 cm) N0-1mi; margins 2 mm; HG 1 2; age >35 years; ER or PgR pos.; EIC and LVI: excluded; ILC: allowed Technique of PBI Median FU (years) LR (%) PBI WBI HDR/PDR BT RTOG (Arthur et al. 2008) Kiel-Budapest MammoSite Trial (Niehoff et al. 2006) Örebro Med. Center (Johansson et al. 2009) T1 2 ( 3 cm) N0-1 (1 3 pos. nodes); clear margins; ILC, DCIS and EIC: excluded T1 ( 2 cm) N0; margins 5 mm; age 60 years; HG 1 2; ILC, DCIS and EIC: excluded T1 2 N0-1 (1 3 pos. nodes); clear margins; age 40 years; EIC: excluded, ILC and LVI: allowed LDR/HDR BT MammoSite BT PDR BT PBI partial breast irradiation, FU follow-up time, LR rate of local recurrence, WBI whole breast irradiation, LDR low-dose rate, BT brachytherapy, ELE electrons, HDR high-dose rate, PDR pulsed-dose rate, ILC invasive lobular carcinoma, DCIS ductal carcinoma in situ, HG histological grade, EIC extensive intraductal component, LVI lympho-vascular invasion, ER oestrogen receptor, PgR progesterone receptor a Studies involving matched-pair analysis

9 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy 219 (Antonucci et al. 2009; Vicini et al. 1997, 2007a; Vicini and Arthur 2005). Between 1993 and 2001, 199 consecutive patients were treated with 50 Gy interstitial LDR (n = 120) or HDR (n = 79) BT. In the latter group, a total dose of 32 Gy in 8 fractions (n = 71) or of 34 Gy in 10 fractions (n = 8) was delivered. Eligibility criteria included an age of >40 years, infiltrating ductal carcinoma <3 cm in diameter, negative surgical margins and negative or 1 3 positive axillary nodes. Patients with an extensive intraductal component (EIC), pure infiltrating lobular histology, pure DCIS or clinically significant areas of lobular carcinoma in situ were excluded. All implants were designed to irradiate the lumpectomy cavity plus at least a surrounding 1 2 cm margin. The last updated report from Antonucci et al. (2009) revealed that, at a median follow-up of 9.6 years, a total of 8 ipsilateral breast failures (4%) were observed, translating into a 10-year actuarial rate of 5%. The results on BT patients were compared with those on a matched cohort of 199 patients treated with conventional WBI at the same institution. There were no statistically significant differences in the 10-year actuarial rates of LR or regional recurrence (Antonucci et al. 2009) Hungarian National Institiute of Oncology (HNIO) Phase II Study Between 1996 and 1998, 45 selected patients with early-stage invasive breast cancer were treated with APBI through the use of interstitial HDR implants at the HNIO, Budapest (Polgár et al. 1999, 2002, 2004, 2005, 2008, 2009, 2010a; Polgár and Major 2009). Patients were eligible for BT alone if they met all of the following conditions: unifocal tumour; tumour size 20 mm (pt1); microscopically clear surgical margins; pathologically negative axillary nodes or only axillary micrometastases (pn1mi); histological grade 1 or 2; and technical suitability for breast implantation. Exclusion criteria were: pure DCIS or lobular carcinoma in situ (ptis); invasive lobular carcinoma; or the presence of an EIC. During surgery, the boundaries of the excision cavity were marked with titanium clips. Implantation was performed under local anaesthesia 4 6 weeks after surgery. The planning target volume (PTV) was defined as the excision cavity (delineated by the surgical clips) plus a margin of 1 2 cm. Single-, double- and triple-plane implants were perfomed on 3, 34 and 8 patients (7, 75 and 18%), respectively. A total dose of 30.3 Gy (n = 8) or 36.4 Gy (n = 37) in 7 fractions was delivered to the PTV over 4 days. The mean volume encompassed by the 100% isodose surface was 50 cm 3. Only 7 patients (16%) received adjuvant tamoxifen therapy. A 12-year update of this study was reported, including comparison with results of a control group treated during the same period with conventional breast-conserving therapy (Polgár et al. 2004, 2008, 2010a; Polgár and Major 2009). The control group comprised 80 consecutive patients who met the eligibilty criteria for APBI, but who were treated with 50 Gy WBI with (n = 36) or without (n = 44) a Gy tumour bed boost. The 12-year actuarial rate of LR was not significantly different between the patients treated with APBI (9.3%) and those with WBI (11.1%). There were no significant differences in either the 12-year probability of disease-free survival (75 and 74%, respectively) or the cancer-specific survival (91 and 89%,

10 220 C. Polgár respectively). The rate of excellent or good cosmetic results was 78% in the APBI group and 67% in the control group (p = 0.045). Similar incidences of fat necrosis were identified in the APBI (38%) and control (31%) groups (p = NS) Örebro Series The first APBI study in which pulsed-dose-rate (PDR) BT was used was begun in December 1993 at the Örebro Medical Centre in Sweden (Johansson et al. 2009). Inclusion criteria included an age of 40 years with a unifocal breast cancer measuring 5 cm without an EIC, which was excised with clear inked margins, and up to 3 positive axillary lymph nodes at maximum. Free-hand plastic tube implants were used to cover the PTV defined as the excision cavity plus 3 cm margins. Fifty patients were treated to a total dose of 50 Gy, using pulses of 0.83 Gy delivered over 5 days. At a median follow-up time of 86 months, the 7-year actuarial LR rate was 4% German-Austrian Multicentre Phase II APBI Trial In 2000, two German (Erlangen and Leipzig) and two Austrian (Vienna and Linz) institutions decided to start the first European multi-institutional phase II trial to investigate the efficacy and safety of HDR/PDR multicatheter APBI (Ott et al. 2007; Strnad et al. 2004, 2010). The four participating centres recruited 274 patients between 2000 and Patients were eligible for APBI if they had a tumour diameter of 3 cm, complete resection with clear margins of 2 mm, pathologically negative axillary lymph nodes, or a singular nodal micrometastasis (pn1mi), hormone receptor-positive tumours, and a patient age 35 years. Patients were excluded from the protocol if they exhibited a multicentric invasive growth pattern, poorly differentiated tumours, residual microcalcifications, EIC or lymph vessel invasion. Among the 274 patients, 175 (64%) received PDR and 99 (36%) HDR BT. the prescribed reference dose in the PDR BT group was 49.8 Gy in 83 pulses of 0.6 Gy each hour. The prescribed reference dose for HDR BT was 32 Gy in 8 fractions of 4 Gy, twice daily. The total treatment time for both groups was 5 days. The PTV was confined to the tumour bed plus a safety margin of 2 3 cm in each direction. Two- or three-plane implants were used in 58 and 42%, respectively. The mean implant volume enclosed by the 85% reference dose was 75 cm 3. The most recent update of this study indicated that 8 patients (2.9%) had developed recurrence in the ipsilateral breast after a median follow-up of 63 months, yielding a 5-year actuarial LR rate of 2% (Strnad et al. 2010) Radiation Therapy Oncology Group (RTOG) Phase II APBI Trial The success of single-institution phase I-II APBI studies stimulated the RTOG to conduct a multi-institutional phase II trial of the use of multicatheter BT as the

11 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy 221 sole method of radiotherapy after BCS (Arthur et al. 2008). Eligibility criteria included unicentric infiltrating non-lobular breast carcinomas 3 cm that had been resected with clear margins, with 0 3 positive axillary nodes without extracapsular extension. Ineligibility criteria included the presence of an EIC or lobular components. Between 1997 and 2000, 99 eligible patients were enrolled from 11 institutions. Two-thirds of the patients (n = 66) received HDR BT with a prescribed dose of 34 Gy in 10 fractions, while one-third (n = 33) were treated with 45 Gy LDR BT. The PTV was defined as a 2 cm margin peripheral to the cavity and 1 cm anteriorly and posteriorly. At a median follow-up of 6.7 years, the estimated 5-year LR rate for the entire cohort was 4%. It is noteworthy that patients of all ages were eligible for participation in the study. Of 6 LRs, 4 occurred in patients younger than 50 years. The crude rate of LR for patients below and above the age of 50 years was 19% and 2.6%, respectively APBI Trials Using the MammoSite and Hybrid BT Applicators APBI with interstitial BT using multicatheter systems requires the special expertise of all the members of staff. To decrease the existing barrier against the wide spread use of multicatheter BT, a new and simple BT applicator was developed in the USA (Keisch et al. 2003). The MammoSite Radiation Therapy System (RTS) is a duallumen spherical balloon catheter (Figs. 9.1 and 9.2). One lumen allows inflation of the balloon to a diameter of 4 5 cm, and the other provides a pathway for the 192 Ir source. The advantage of this system is that only one applicator is to be implanted to deliver fractionated HDR BT to the tumour bed as compared with interstitial BT, which requires the implantation of catheters. Since 2002, this system has been available for commercial use. In the USA, the MammoSite system has been implemented by a number of institutions, and to date more than 30,000 women have been treated with the use of the device (Smith et al. 2009). So far, only two groups Fig. 9.1 The MammoSite brachytherapy applicator

12 222 C. Polgár Fig. 9.2 Dose distribution using the MammoSite brachytherapy applicator. The dose is prescribed to 1 cm distance from the surface of the balloon applicator have reported their results with a follow-up period beyond 5 years (see Table 9.4). In the initial FDA MammoSite APBI trial, 43 of 70 eligible patients (61%) were treated from May 2000 to October 2001 (Benitez et al. 2007; Keisch et al. 2003). The entry criteria in the study were unifocal invasive ductal carcinoma, a tumour size of 2 cm, an age of 45 years, the absence of an EIC, a cavity size of 3 cm, negative axillary nodes and clear final surgical margins. A minimum balloon-toskin surface distance of 5 mm was required. A dose of 34 Gy was delivered in 10 fractions over 5 days, prescribed to 1 cm from the applicator surface, using HDR BT. At a median follow-up of 5.5 years, no LRs or regional failures had occurred. A good or excellent cosmetic outcome was achieved in 81% of the cases, but the rate was only 67% among the patients with <7 mm skin spacing. Furthermore, a very high rate of teleangiectasia (39.5%) was identified, and the rate was exceptionally high (75%) in patients with <7 mm skin spacing. In the early European studies, altogether 54 patients were enrolled into the MammoSite APBI trials (Niehoff et al. 2006; Polgár et al. 2009). The eligibility criteria were an age of 60 years (age 40 years for boost); a tumour size of 2 cm ( 2.5 cm for boost); invasive ductal histology; grade 1 2 (grade 2 3 for boost); free surgical margins of 5 mm (negative margins for boost); applicator placement within 10 weeks of the final lumpectomy procedure; an excision cavity with one dimension of 3 cm. In contrast with the US studies, a skin-to-balloon distance of 7 mm was demanded. Exclusion criteria were the presence of EIC, pure intraductal cancer, lobular histology, multifocal or multicentric lesions. For MammoSite therapy alone, a total dose of 34 Gy in 10 fractions was delivered over 5 7 days. In the boost group, a total dose of Gy was delivered with a dose per fraction of 2.5 Gy over 2 4 days. Of the 54 patients implanted with the catheter, 10 (18.5%)

13 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy 223 had to be excluded from the clinical trial. At the final decision, 28 patients were eligible for BT alone and 16 patients were treated with boost BT followed by WBI. No LR had occurred after a mean follow-up of 14 months (range: 3 31 months) (Niehoff et al. 2006; Polgár et al. 2009). At a median of 5 years, a teleangiectasia rate of 54% (64% in the primary, and 46% in the boost group) was reported (Polgár and Major 2009; Polgár et al. 2009). Therefore, in Europe, avoidance of use of the MammoSite system was suggested for patients with a balloon-to-skin distance of 15 mm. Due to the flexibility for dose shaping with multicatheter BT, instead of using the MammoSite applicator, we prefer interstitial implants for those patients with an inadequate (<15 mm) skin distance. Several new BT devices have recently been developed that combine the advantages of multicatheter and MammoSite balloon BT, blending the versatility and flexibility of interstitial BT for dose shaping with the simplicity and convenience of a single-entry device (Beriwal et al. 2008; Dickler et al. 2009; Scanderbeg et al. 2009; Vicini et al. 2010a). Each of the SAVI (Strut-Adjusted Volume Implant), the SenoRx Contura (Fig. 9.3) and the ClearPath applicators is a marriage of these two techniques and uses multiple struts, which can be differentially loaded to maximize the tumour bed dose and minimize the normal tissue dose. The limited experience with hybrid breast BT applicators suggests that the skin dose can be reduced significantly without comprising the PTV coverage (Beriwal et al. 2008; Dickler et al. 2009; Scanderbeg et al. 2009; Vicini et al. 2010a). Nevertheless, the use of hybrid breast BT devices has a potential to increase the applicability of APBI in patients with an inadequate balloon-to-skin distance. In view of the American and European experience, the MammoSite and other recently developed hybrid breast BT devices have rapidly gained acceptance and popularity both by the patients and by their physicians. Obviously, these applicators offer an alternative method of APBI for a selected group of patients. Unfortunately, in most European countries the high costs of these applicators are not reimbursed by the health insurance system. Fig. 9.3 SenoRx Contura multilumen balloon applicator

14 224 C. Polgár APBI Using Permanent LDR Seed Implants A new technique of APBI using 103 Pd permanent seed implants was recently implemented by Pignol et al. (2006). Investigators from the University of Toronto implanted 16 patients with a mean of 70 seeds per patient. A dose of 90 Gy was prescribed as the minimal peripheral dose set to cover the PTV, defined as the lumpectomy cavity plus a margin of 1 cm. Patients with a PTV of >70 cm 3 were excluded to avoid the implantation of an excessive amount of radioactivity. In spite of the feasibility of breast seed implantation, only 52% of eligible patients received the treatment. Thus, further studies are necessary to determine the practicability, efficacy and risks associated with this new technique of APBI Contemporary Phase II APBI Trials Using Teletherapy Techniques Another alternative for PBI is the use of teletherapy. Since BT requires extra technical background and special skills, the non-invasive external beam APBI techniques comprise a more accessible and convenient treatment option, with several advantages, but also disadvantages as compared with the BT methods (Fig. 9.4) New York University Experience with 3-D Conformal External Beam APBI Formenti et al. (Formenti 2005) have explored the treatment of women with 3-D conformal external beam APBI in the prone position in order to minimize the ef- Fig D conformal external beam accelerated partial breast irradiation. Five-field noncoplanar beam arrangement with 6 MV photons in supine position

15 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy 225 fect of respiratory motion. Planning CT in the prone position was performed on a dedicated table. The PTV was defined as the postoperative cavity plus a margin of 1.5 cm in all directions. A total dose of 30 Gy at 6 Gy/fraction was delivered in 5 fractions within 10 days. At a median follow-up of 18 months, none of the patients exhibited local recurrence William Beaumont Hospital Experience with 3-D Conformal External Beam APBI Vicini et al. (2007b) carried out 3-D conformal external beam APBI with a four- or five-field non-coplanar beam arrangement with 6 MV photons, the treated patients occupying the supine position. The clinical target volume (CTV) definition was similar to that for BT at 15 mm beyond the surgical cavity; however, an additional 10 mm was added to form the PTV. A total dose of 34 or 38.5 Gy in 10 fractions was delivered over 5 days. The group has recently updated the results on 94 patients (Chen et al. 2010). After a median follow-up of 4.2 years, only one local recurrence had occurred, resulting in a 4-year actuarial LR rate of 1.1% Radiation Therapy Oncology Group (RTOG) 0319 Phase II 3-D Conformal External Beam APBI Trial On the basis of the Beaumont experience reported by Vicini et al. (Chen et al. 2010; Vicini et al. 2007b), a multicentre phase II study, RTOG 0319, examined the feasibility of 3-D conformal external beam APBI (Vicini et al. 2010c). Patients were treated with a similar 3-D conformal external beam APBI technique to a dose of 38.5 Gy in 10 fractions over 5 days. In the preliminary analysis of this study, APBI with 3-D conformal external beam radiotherapy was shown to be technically feasible and reproducible in a multicentre trial. Among the 58 enrolled patients, 52 were eligible and evaluable as regards efficacy and toxicity assessments (Vicini et al. 2010c). At a median follow-up of 4.5 years, a total of 3 ipsilateral LRs were recorded, for a 4-year actuarial rate of 6%. Only 2 patients (4%) developed treatmentrelated grade 3-toxicity: 1 patient with fibrosis and teleangiectasia of grade 3, and 1 patient with radiation dermatitis and myositis of grade Other External Beam APBI Delivery Techniques The techniques of intensity-modulated radiation therapy (IMRT), image-guided radiotherapy (IGRT), helical tomotherapy, and proton therapy were recently tested in APBI (Hui et al. 2004; Leonard et al. 2010; Livi et al. 2010; Taghian et al. 2006). The preliminary results showed improved normal tissue sparing and target volume homogeneity as compared with 3-D conformal external beam APBI techniques.

16 226 C. Polgár Phase III APBI Trials In parallel with the increasing evidence obtained from phase I-II studies supporting the use of APBI for selected early-stage breast cancer patients, at least 8 phase III trials comparing different techniques of APBI with conventional WBI have been initiated in the past decade in Europe, Canada and the USA (Table 9.5). Utilizing on the available evidence obtained from published APBI studies, both the American Society for Therapeutic Radiology and Oncology (ASTRO) and the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) recently published their recommendations for patient selection for APBI (Polgár et al. 2010a; Smith et al. 2009) Hungarian National Institute of Oncology (HNIO) Phase III APBI Trial The encouraging results of the first Hungarian study prompted a randomized study at the same institution in Budapest between 1998 and 2004 (Polgár et al. 2002, 2005, 2007, 2008, 2009; Polgár and Major 2009). The initial eligibility criteria were Table 9.5 Overview of the prospective randomized clinical studies evaluating APBI Study Participants APBI technique Activation date Accrual goal (status) Hungarian HNIO, Budapest HDR BT 7/ (closed: 5/2004) ELIOT EIO, Milan IORT, electrons 11/2000 1,200 (closed: 12/2007) GEC-ESTRO European multicentre HDR/PDR BT 5/2004 1,233 (closed: 7/2009) TARGIT British-Australian multicentre IORT, 50 kv photons 3/2000 2,232 (closed: 11/2009) NSABP- B39/ RTOG American multicentre HDR BT/ Mamosite/ 3-D-CRT 3/2005 4,300 (ongoing) Italian Florence University IMRT/IGRT 9/ (ongoing) RAPID Canadian multicentre 3-D-CRT 2/2006 2,128 (ongoing) IMPORT British multicentre IMRT 9/2006 1,935 (ongoing) LOW APBI accelerated partial breast irradiation, HNIO Hungarian National Institute of Oncology, HDR BT high-dose-rate brachytherapy, ELIOT ELectron IntraOperative Therapy, EIO European Institute of Oncology, IORT intraoperative radiotherapy, GEC-ESTRO Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology, PDR pulsed-dose rate, TARGIT TARGeted Intraoperative Therapy, NSABP National Adjuvant Breast and Bowel Project, RTOG Radiation Therapy Oncology Group, 3-D-CRT 3-dimensional conformal radiotherapy, RAPID Randomized trial of Accelerated Partial breast IrraDiation, IMPORT LOW Intensity Modulated Partial Organ RadioTherapy, IMRT intensity-modulated radiotherapy, IGRT image-guided radiotherapy

17 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy 227 similar to those for the previous study, although following the publication of the findings of the EORTC boost trial in 2001, patients aged 40 years were excluded. In addition, the trial allowed patients with breasts that were technically unsuitable for interstitial implantation to be enrolled and treated with an external beam (EB) approach. By May 2004, 258 eligible patients had been randomized to receive either 50 Gy WBI (n = 130) or PBI (n = 128). The patients in the latter arm received either 36.4 Gy (given in 7 fractions of 5.2 Gy over 4 days) with HDR multicatheter BT (n = 87) or limited-field electron irradiation (n = 40) as a dose of 50 Gy in 25 fractions. One-, two-, three- or four-plane implants were performed in 1 (1%), 47 (54%), 38 (44%) and 1 (1%) patients, respectively. The mean volume encompassed by the reference isodose surface was 62 cm 3. A majority of the patients in both arms (70%) received adjuvant hormone therapy. During the years of the study, a CT image-based 3-D conformal BT technique was implemented to avoid geographical miss (Figs. 9.5 and 9.6). Fig. 9.5 Interstitial multicatheter brachytherapy implant Fig. 9.6 Postimplant target volume definition for multicatheter brachytherapy. Red line = visible seroma; yellow line = excision cavity; green line = planning target volume; blue circles = surgical clips

18 228 C. Polgár The 5-year results of the Hungarian randomized study were published in 2007 (Polgár et al. 2007). In the most recent analysis, at a median follow-up time of 6.8 years, there was no significant difference between the two treatment arms in local and regional tumour control, or disease-free, cancer-specific or distant metastasisfree survival (Polgár et al. 2008, 2009; Polgár and Major 2009). The rate of an excellent to good cosmetic outcome was 77% in the PBI group (81% after HDR BT and 68% after EB) and 65% in the control group (p = 0.024) European (GEC-ESTRO) Multicentre Randomized APBI Trial The success of the Hungarian and German-Austrian APBI studies led to the development of a multicentre phase III APBI protocol by the Breast Cancer Working Group of the GEC-ESTRO (Polgár et al. 2005, 2010a; Polgár and Major 2009). Only interstitial HDR or PDR BT was allowed for the APBI arm of this European multicentre phase III trial. Between May 2004 and July 2009, 1233 patients were randomized in 16 centres in 7 European countries. The patients in the control group were treated with 50 Gy WBI plus a 10 Gy electron boost. The patients in the APBI arm were treated with HDR or PDR multicatheter BT. The primary end-point of the study is LR as a first event within 5 years. The secondary end-points address overall, disease-free and distant metastasis-free survival, the incidence of contralateral breast cancer, early and late side-effects, cosmesis and the quality of life. Eligibility criteria included unifocal DCIS or invasive carcinoma of the breast, a tumour size of 3 cm, microscopic negative margins of 2 mm (5 mm for DCIS or invasive lobular carcinoma), no EIC, no lymphovascular invasion, not more than one micrometastasis in the axillary lymph nodes (pn1mi), and a patient age of 40 years. The QA program for partial breast BT included preimplant PTV definition by surgical clips and/or preimplant CT image-based preplanning of the implant geometry. The PTV was defined as the excision cavity plus a 2 cm margin minus the minimum clear pathological margin. Postimplant CT scans were mandatory for the documentation of target coverage and dose homogeneity. Acceptable treatment parameters for CT image-based treatment planning include: DVH analysis of target coverage, confirming that the prescribed dose covers 90% of the PTV (coverage index 0.9) A dose non-uniformity ratio (DNR) 0.35 A maximum skin dose of <70% of the prescribed dose American (NSABP B-39/RTOG 0413) Multicentre Randomized APBI Trial The American multicentre phase III trial involving an investigation of APBI was initiated in March 2005 by the National Surgical Adjuvant Breast and Bowel Project

19 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy 229 (NSABP) together with the RTOG (Vicini and Arthur 2005). Patients were randomized between standard WBI and APBI. The latter may be delivered with any of the three techniques of multicatheter HDR BT, MammoSite BT or 3-D conformal external beam RT. Eligibility criteria include unicentric DCIS or invasive carcinoma allowing microscopic multifocality confined to one quadrant of the breast, a tumour size of 3 cm, microscopic negative margins on the NSABP criteria (no tumour on inked margins), and not more than 3 positive axillary lymph nodes (pn0 1a) without extracapsular extension. In contrast with the GEC-ESTRO trial, patients aged <40 years with tumours excised with close (but clear) surgical margins or containing an EIC are eligible for the NSABP/RTOG trial, as are those with 1 3 positive nodes. Due to the rapid enrolment of low-risk patients by multiple American centres, the original accrual goal (3,000 patients) was increased to 4,300. In December 2006, the trial closed enrolment to low-risk patients, thereby limiting the further accrual of patients satisfying one or more of the high-risk criteria, including an age of <50 years, oestrogen receptor negativity, or 1 3 positive nodes The ELIOT Phase III APBI Trial The promising results of a previous phase I-II study, between December 2000 and December 2007, the Milan group conducted a prospective randomized phase III trial to compare conventional WBI (50 Gy plus a 10 Gy boost to the tumour bed) with a single dose of 21 Gy intraoperative radiotherapy (IORT), using 3 9 MeV electron beams (Orecchia et al. 2009). Eligible patients were aged >48 years and affected by unicentric infiltrating carcinomas of the breast with a maximum diameter of 2.5 cm. Overall, 1,306 patients were recruited. The 5-year results of this randomized study will help determine whether single-fraction IORT can replace conventional WBI in this subgroup of women APBI Using Intraoperative 50 kv Photons The TARGIT Phase III APBI Trial IORT with a single fraction of 50 kv photons was implemented by Vaidya et al. (2010) in The Intrabeam device provides a point source of low-energy X- rays at the tip of a 3.2 mm diameter tube that is placed at the centre of a spherical tumour bed applicator. When the Intrabeam device is used, the surface of the tumour bed typically receives 20 Gy, which is attenuated to 5 7 Gy at a depth of 1 cm. After safely piloting the new technique, the same group launched a phase III trial (TARGIT-A trial) in Overall, 1,113 patients were randomly allocated to IORT and 1,119 to WBI. At 4 years, there were 6 LRs in the IORT group and 5 in the WBI group. The Kaplan-Meier estimate of LR in the conserved breast at 4 years was 1.20% in the IORT and 0.95% in the WBI group (p = 0.41). However, only 854 of the 1,113 patients (77%) allocated to the investigational (APBI) arm received

20 230 C. Polgár IORT alone: 100 patients did not receive the allocated treatment (61 received WBI, 31 underwent mastectomy, and 8 received no radiotherapy), and an additional 142 patients received WBI after IORT. The design of this study (allowing patrticipating centres to stipulate local policy for giving WBI after IORT in the APBI group) may therefore be criticized. 9.3 Accelerated Whole Breast Irradiation (AWBI) The standard radiotherapy regimen after BCS for early breast cancer delivers 25 daily fractions of 2 Gy to a total dose of 50 Gy over 5 weeks. Alternative fractionation schedules based on a lower total dose delivered in a smaller number of larger fractions (AWBI) were introduced in the UK and Canada decades ago on an empirical basis (The START Trialists Group 2008a, b). Later, formal phase III studies were conducted to compare the efficacy and safety of AWBI with those of to the standard fractionation schedule (Table 9.6) (Hopwood et al. 2010; Owen et al. 2006; The START Trialists Group 2008a, b; Whelan et al. 2010; Yarnold et al. 2005; Yarnold and Haviland 2010) Royal Marsden Hospital/Gloucestershire Oncology Centre (ROM/GOC) AWBI Trial In the period , Owen et al. (2006) and Yarnold et al. (2005) randomly assigned 1,410 women with invasive breast cancer who had BCS to receive 50 Gy radiotherapy given in 25 fractions, 39 Gy given in 13 fractions, or 42.9 Gy given in 13 fractions, all given over 5 weeks. The primary end-point was the breast appearance. After a minimum of 5 years of follow-up, the risk of any change in breast appearance after 50 Gy/25 fractions, 39 Gy/13 fractions or 42.9 Gy/13 fractions was 40%, 30% and 46%, respectively; an α/β value for breast fibrosis of around 3 Gy was estimated (Yarnold et al. 2005). After a median follow-up of 9.7 years, the incidence of LR at 10 years was 12.1% in the 50 Gy group, 14.8% in the 39 Gy group, and 9.6% in the 42.9 Gy group (Owen et al. 2006) Ontario Clinal Oncology Group (OCOG) AWBI Trial Between 1993 and 1996, Whelan et al. (2010) randomized 1,234 women to receive WBI of 42.5 Gy in 16 fractions over 22 days versus 50 Gy in 25 fractions over 35 days. The primary end-point was LR in the treated breast. Secondary outcomes were distant recurrence, death from any cause, breast cosmesis and late radiation

21 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy 231 Table 9.6 Prospective randomized clinical studies testing accelerated whole breast irradiation Study Study period Fractionation Patient schemes n Median FU (years) 5-y LR (%) 10-y LR (%) RMH/GOC (Owen et al. 2006; Yarnold , et al. 2005) 25 2 Gy 7.9 a Gy 9.1 a Gy 7.1 a 9.6 OCOG (Whelan et al. 2010) , Gy Gy START A (The START Trialists Group 2008a) START B (The START Trialists Group 2008b) , Gy 3.6 a NR Gy 3.5 a NR 13 3 Gy 5.2 a NR , Gy 3.3 a NR Gy 2.2 a NR UK FAST (Yarnold and Haviland 2010) Gy NR NR Gy NR NR 5 6 Gy NR NR FU follow-up time, LR rate of local recurrence, RMH/GOC Royal Marsden Hospital/Gloucestershire Oncology Centre, OCOG Ontario Clinical Oncology Group, START Standardization of Breast Radiotherapy, NR not reported a Rate of locoregional recurrence

22 232 C. Polgár toxicity. The 5- and 10-year LR rates were 2.8% and 6.2% in the accelerated arm and 3.2% and 6.7% in the conventional fractionation arm. No significant difference was found in any of the secondary end-points START A and B AWBI Trials Following the results of the ROM/GOC trial, Yarnold et al. (Hopwood et al. 2010; The START Trialists Group 2008a, b) conducted two parallel randomized trials (START A and B) of radiotherapy hypofractionation for the treatment of early breast cancer. In the START A trial, 2,236 women were randomly assigned after BCS to receive 50 Gy in 25 fractions versus 41.6 or 39 Gy in 13 fractions of 3.2 or 3 Gy, respectively, over 5 weeks (Hopwood et al. 2010; The START Trialists Group 2008a). After a median follow-up of 5.1 years, the rate of locoregional recurrence (LRR) at 5 years was 3.6% after 50 Gy, 3.5% after 41.6 Gy, and 5.2% after 39 Gy. The assessment of the cosmetic outcome by both the physicians and the patients indicated the lowest rate of late adverse effects in the 39 Gy arm. In the START B trial, 2,215 women were randomly assigned to receive 50 Gy in 25 fractions over 5 weeks or 40 Gy in 15 fractions of 2.67 Gy over 3 weeks (Hopwood et al. 2010; The START Trialists Group 2008b). After a median follow-up of 6 years, the rate of LRR at 5 years was 2.2% in the 40 Gy group and 3.3% in the 50 Gy group. Again, the late side-effects of radiation were lower in the 40 Gy arm as compared with the standard radiotherapy arm. The authors concluded that AWBI seems to offer similar locoregional tumour control and late adverse effects at least as favourable as those with the standard schedule of 50 Gy WBI in 25 fractions UK FAST AWBI Trial In the most recent phase III trial by Yarnold et al. (Yarnold and Haviland 2010), 915 patients were randomized to 50 Gy WBI in 25 fractions over 5 weeks or to a dose of 28.5 Gy or 30 Gy given in 5 weekly fractions of 5.7 or 6 Gy, respectively. Efficacy results have not yet been published. At a median follow-up of 28 months, the 5-fraction regimen of 5.7 Gy appeared as safe as the standard schedule. 9.4 Omission of Radiotherapy after BCS The effectiveness of radiotherapy in reducing LR after BCS in unselected patients with early stage invasive and in situ breast cancer has been demonstrated in multiple randomized trials (Clark et al. 1992, 1996; Fisher et al. 1985, 1993, 1995, 1999, 2001; Ford et al. 2006; Forrest et al. 1996; Liljegren et al. 1994,

23 9 Radiotherapy A New Approach to Risk-Adapted Selective Radiotherapy ; Renton et al. 1996; Veronesi et al. 1993, 2001; Bijker et al. 2006; Emdin et al. 2006; Houghton et al. 2003; Julien et al. 2000). However, there is continuous interest in identifying patients at low risk for LR who could safely avoid radiotherapy (Fisher et al. 2002a, 2007; Fyles et al. 2004; Holli et al. 2001; Hughes et al. 2004; Lim et al. 2006; Malmström et al. 2003; Pötter et al. 2007; Schnitt et al. 1996; Winzer et al. 2004). The results of these trials are summarized in Table 9.7. Obviously, all but one trial failed to identify a subgroup of patients for whom radiotherapy of the conserved breast could be safely omitted. In the CALGB (Cancer and Leukemia Group B) study, only women aged >70 years with oestrogen receptor-positive, stage I (T1 N0 M0) breast cancer excised with negative surgical margins were randomized to receive tamoxifen plus radiotherapy or tamoxifen alone (Hughes et al. 2004). The only significant difference between the two groups was in the rate of LR at 5 years: 1% in the group given tamoxifen plus radiotherapy, and 4% in the group given TAM alone. However, there was no significant difference between the two groups as regards the rates of mastectomy for LR, distant metastasis, or the 5-year overall survival rate. The authors therefore concluded that both radiotherapy plus tamoxifen and tamoxifen without radiotherapy appeared to be appropriate for women aged 70 years with clinical stage I, oestrogen receptor-positive breast cancers. 9.5 Summary The Future of Risk-Adapted Radiotherapy After BCS During the past forty years BCS followed by WBI has become the standard of care for the treatment of early-stage (St. 0-I-II) breast carcinoma (Bartelink et al. 2007; Fisher et al. 2002a; Veronesi et al. 2002). Several randomized clinical trials have proved that WBI following BCS significantly decreases the risk of recurrence in the ipsilateral breast, and increases the overall survival (at least for invasive cancers) (Clark et al. 1992, 1996; Fisher et al. 1985, 1993, 1995, 1999, 2001; Ford et al. 2006; Forrest et al. 1996; Liljegren et al. 1994, 1999; Renton et al. 1996; Veronesi et al. 1993, 2001; Bijker et al. 2006; Emdin et al. 2006; Houghton et al. 2003; Julien et al. 2000). With the advent of breast screening, the incidence of breast carcinomas with more favourable prognostic characteristics (including in situ, microinvasive and invasive tumours measuring up to 15 mm) has increased significantly. This change in the prognostic profile of newly diagnosed breast cancers has opened up new horizons for clinical research seeking individual risk-adapted protocols for breast cancer radiotherapy. The evidence obtained from contemporary randomized trials questions the one fit for all treatment (e.g. the routine use of WBI) for all patients after BCS. The anticipated future of individual risk-adapted RT after BCS is summarized in Table 9.8. Molecular profiling and simultaneous evaluation of multiple genes will be of special interest in the future and might help to further refine individual risk-adapted local management strategies for patients with earlystage breast cancer.