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ntraoperative Radiotherapy Followingumpectomy for Breast Cancer

rederick M. Dirbas* and Kathleen C. Horst†

Intraoperative radiotherapy (IORT) is a promising approach for delivering accelerated,partial breast irradiation (APBI). Condensing the entire therapeutic dose into a singlefraction, delivering the treatment at the time of lumpectomy in the operating room, and withthe ability to spare normal surrounding tissue to a greater extent than perhaps any otherform of APBI, IORT offers many potential benefits. Whether a single fraction is able toprovide effective local control, and whether long term tissue tolerance to a large singledose is acceptable, are the greatest concerns for this approach. Breast IORT trials con-ducted thus far are encouraging. This review will first describe the clinical trials thatprovided the groundwork for single-fraction breast IORT, and will then summarize ongoingphase I/II and phase III clinical trials evaluating this potentially safe and effective form ofAPBI.Semin Breast Dis 10:26-33 © 2007 Elsevier Inc. All rights reserved.

KEYWORDS breast cancer, lumpectomy, accelerated, partial breast irradiation, intraoperativeradiotherapy, IORT

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mong the different methods now available for deliveringaccelerated, partial breast irradiation (APBI), single frac-

ion, intraoperative radiotherapy (IORT) may offer the mostbbreviated and targeted form of treatment. Radiotherapy isot only delivered in one dose in the operating room at theame time as lumpectomy, but is also visually directed at theumpectomy cavity margins by the surgeon and radiationncology team. This leaves little chance for clip migration, orostoperative tissue changes to blur the definition of targetolume as is possible with post-surgical forms of APBI.1 WithORT it is possible to exclude skin, normal breast tissue,uscle, bone, heart, and lung from the target volume, which

s difficult and sometimes impossible with other forms of aBI. And, data emerging from the laboratory suggest that aingle fraction of high-dose radiotherapy applied to tumorells, stroma, and in particular, tumor endothelial cells, couldn fact be more lethal to a malignant lesion than fractionatedosing.2 Accordingly, single-fraction IORT is potentially theost convenient form of PBI for patients, could provide theost accurate targeting of tissue at risk, might spare normal

tanford Cancer Center, *Department of Surgery andDepartment of Radiation Oncology, Stanford University School of Medi-

cine, Stanford, CA.ddress reprint requests to Frederick M. Dirbas, MD, Stanford Cancer Cen-

ter, 875 Blake Wilbur Drive, CC2235, Stanford, CA 94305. E-mail:

adirbas@stanford.edu

6 1092-4450/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1053/j.sembd.2007.08.001

issue away from the lumpectomy cavity margins to a greaterxtent than other forms of a PBI, and could be as, or more,ffective in eradicating residual tumor cells within the targetolume.

In contrast to these potential benefits, the concept of con-ensing an entire 6- to 7-week course of radiotherapy into aingle dose in the operating room is daunting and raiseseveral concerns. For example, IORT is usually delivered inhe absence of final pathology for tumor histology, margins,nd lymph nodes. In addition, whereas visual creation of thearget volume is appealing and customary for all forms ofORT, this approach represents a significant departure fromhe conventional image-guided treatment planning that isow commonplace for almost all forms of breast radiother-py, whether a PBI, conventional whole breast, external beamadiotherapy (WB-XRT), or the post WB-XRT “boost” dose.n addition, the single-fraction approach might not effec-ively eradicate residual tumor cells near the primary siteompared with fractionated dosing, despite laboratory stud-es demonstrating otherwise. And the high dose used in theingle fraction could produce significant tissue toxicity eitherarly or many years after treatment. All of these risks haveontributed to significant inertia surrounding the initiation ofingle fraction, breast IORT trials.3,4

The promise of single fraction postlumpectomy IORT istrong, however. And so, despite the concerns mentioned

bove, a small number of single-institution trials were devel-

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IORT following partial mastectomy 27

ped to test the concept. Short-term results from these stud-es have provided preliminary data supporting the safety andffectiveness of this approach and encouraged the initiationf additional studies to further test the single fraction, breastORT concept more broadly.

This review will briefly cover early studies using IORT inieu of the standard “boost” dose, as well as a pilot, singleraction IORT study. It will then focus on ongoing, singleraction IORT trials. These later studies were developed

ore recently in the “modern” era of a PBI, based on theatershed brachytherapy studies performed at thechsner Clinic and William Beaumont Hospital, that de-ned new, successful patient selection and treatment plan-ing criteria.5,6 The somewhat diverse single fraction,reast IORT studies that have emerged and are ongoingill be discussed independently due to the differing meth-ds for patient selection, radiotherapy technique, and do-imetry. Study-specific evaluation is necessary, as none,ne, or several of the current single fraction breast IORTpproaches may succeed in providing a safe, effectiveethod for APBI.7

arly Use of Breast IORTnvestigators at the Medical College of Ohio (MCO) were therst to report breast IORT which they used as a substitute forhe breast boost dose. Between 1984 and 1996, the grouperformed lumpectomies and axillary lymph node dissectionALND) in 21 women (mean age 54, range 33-75). Ratherhan closing the breast incision after the lumpectomy, thenvestigators loosely approximated the lumpectomy cavitydges to “draw the lateral margins” into apposition to create aarget volume. Cylindrical applicators ranging in size from.25 inches to 3.5 inches in diameter were then brought ontohe operative field with the tip placed in the incision and theperture directly facing the target volume. Electron beamORT was then delivered to the target volume consisting ofhe lumpectomy cavity margins with 10 Gy (18 patients) or5 Gy (3 patients) with 6, 9, 12, and 16 MeV electrons used

n 4, 9, 5, and 3 patients, respectively. After surgery, patientsere then treated with an additional 45- to 50-Gy dose ofB-XRT given over 5 to 6 weeks using 6 MV photons. Thereere no early complications. Two patients subsequently de-eloped detectable induration at the IORT site, 3 had palpa-le masses, and 1 had microcalcifications. At a median fol-

ow-up of 71 months, there were no local recurrences.8

At the Centre Regional de lutte Contre le Cancer (CRLC,ontpellier, France) a second group of investigators similarly

tilized IORT as the boost method in 50 patients followingartial mastectomy (median age 59, range 37-76) between989 and 1999. Inclusion criteria were T � 3 cm, tumor-freeargins, and clinically normal lymph nodes. Both invasive

obular carcinoma (ILC) and extensive intraductal carcinomaEIC) were allowed. Overall there were 40 T1 tumors and 102 tumors. A total of 41 patients were N0, with 8 having N1odal status. As with the group at MCO, after resection andLND, electron beam IORT with a median dose 10 Gy (9-20

y at 90% isodose) using a median 9 MeV electrons (range p

-13 MeV) was delivered to 1-cm margins of the tumor bedsing collimator cross-sections of 3, 4, or 5 cm (maximumreated cavity margin of approximately 1.5 to 2.5 cm). WB-RT was then delivered beginning 10 to 15 days after surgerysing 2-Gy doses 5 times per week to a total whole breastose of 45 Gy. Most patients had mild induration under the

umpectomy scar that dissipated in 1 to 2 months. There waso grade 3 toxicity. At 9.1 years median follow-up, 2 patientsad developed local recurrences at 8 and 14 years, respec-ively, and there were 6 patients with distant metastases.9

Based on the experience using breast IORT as a substituteor the boost dose, a group from the Roswell Park Cancernstitute (Buffalo, NY) treated a small group of patients usingreast IORT delivered in a single fraction as the sole methodf post-lumpectomy radiotherapy. This pilot trial involved 7omen (age 58, range 43-70) with both stage I (3 patients: 21b and 1 T1c) and stage II disease (4 patients). Women withLC and involved nodes, including extracapsular extension,ere allowed to participate, and tumor-free margins were

equired. After lumpectomy and ALND, which was per-ormed in 6 of 7 patients, the tumor bed was treated withrthovoltage radiation, 120-kVp x-rays on a Picker Zephyr20 machine redesigned for use in a designated OR. Five of 7atients received 15 Gy, whereas 2 of 7 received a 20 Gyurface dose. The group did not report collimator sizes, cav-ty perimeter treated, or whether a beam-stopper was used.o treatment-related complications were noted. At a median

ollow-up of 6 years, the group felt that both the postopera-ive mammograms and cosmetic appearance of the breastere free of signs of IORT. After mean follow-up of 10.1 years

123 months; range 86 to 139), 2 of 7 patients (29%) hadecurred locally. A surgical scar recurrence was noted in 1atient with a T1c lesion (surgical margin � 2 mm) 36onths after treatment, whereas the second patient with

tage IIb disease (T2N1 with 3 of 13 involved lymph nodes)ecurred in the treatment bed at 120 months. Both had beenreated with 15 Gy. These 2 patients underwent mastecto-ies and were disease-free at the time the group’s resultsere reported. Overall, all surviving patients expressed sat-

sfaction with clinical results. Although using a small series ofatients, this group was the first to confirm that the breastould tolerate single fractions of 15-20 Gy using orthovoltageadiation without undue toxicity at 10 years. Although 2 of 7atients had a local recurrence, neither of these patientsould have met the study exclusion criteria (tumor-free mar-in � 2 mm and uninvolved nodes) used by the group atilliam Beaumont Hospital which was the first to report the

ssociation of strict patient selection criteria and low localecurrence rates.10

ngoing Studies with APBIsing Single Fraction IORT

he original pilot efforts with intraoperative breast radio-herapy have evolved into at least five approaches for sin-le fraction APBI with IORT. These techniques differ in

atient selection, equipment, radiotherapy source, dose of

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adiotherapy delivered, and possibly effectiveness. Ac-ordingly, the varying approaches will be discussed inde-endently.

ORT Using Intracavitaryrthovoltage Radiotherapy

nvestigators at the University College Hospital in Londonnitiated a pilot trial with breast IORT in July 1998. Sur-eons and radiation therapists used a novel, mobile, min-ature linear accelerator that is suspended on a gantryIntraBeam™, manufactured by Zeiss, Inc.) to deliver low-nergy radiation (50 kV). The dependent, functional tip ofhe 10-cm by 3.2-mm accelerator, a small probe, is cov-red by one of several interchangeable, variable sized,pherical applicators (2.0- to 5.0-cm diameter), which isowered into the lumpectomy cavity. Dosimetry varies bypplicator tip size with the most commonly used 3.5-cmpplicator sphere delivering 20 Gy at a radius of 1 mmrom the surface, 5 Gy at 10 mm, and 1 Gy at 27 mm.tudy leaders have called this the TARGIT approach (Tar-eted, Intraoperative Radiotherapy).In the operating room, following lumpectomy and sentinel

ode biopsy, the dimensions of the surgical cavity are mea-ured and an appropriately sized applicator sphere is at-ached to the x-ray source. Initially the tip of the applicatorphere was then covered with a Tungsten impregnated cap toct as a beam-stopper against the chest wall, but this is nowarely used as treatment of this margin may help avoid localecurrence and total dose to the underlying lung and/or hearts considered insignificant. A sterile cover is then applied tohe assembled apparatus, which is lowered into the tumored. Surgical margins are brought into conformance with the

Figure 1 Intrabeam device used in TARGIT

pplicator sphere using one or two purse-string sutures and b

kin is drawn away from the applicator shaft without addi-ional dissection (Fig. 1). Irradiation of the breast tissueround the sphere is performed over a 24- to 25-minuteeriod for a 3.5-cm applicator and 30 minutes for a 5-cmpplicator. An update on the U.K. pilot trial in December003 indicated that this device has been used in 22 womenith “low-risk” lesions and who received no other form of

adiotherapy.11

The main advantages of this approach are the portability ofhe device. However, because the radiation dose falls off quiteapidly from the applicator sphere, the dosimetry with thisevice is controversial. Although it is possible that the deviceay achieve effective local control of disease, it is also possi-

le that residual tumor more than a few millimeters awayrom the edge of lumpectomy cavity margin may not receiveherapeutic doses of radiation.

A large, multi-institutional randomized study is now un-er way with the TARGIT technique comparing single frac-ion breast IORT with standard WB-XRT. Inclusion criterianclude age � 50, T � 2 cm, tumor grade � 2, and clear

argins (nontransection), with ILC, EIC, and involvedymph nodes set as exclusion criteria (www.targit.org.uk).In a parallel arm of the study, for women who do not meet allhese inclusion/exclusion criteria, IORT is used in lieu of theoost dose and WB-XRT follows surgery.) At this time, insti-utions from the U.K., Australia, Germany, Italy, and the U.S.re participating.12 Seven hundred seventy-four patientsave been recruited as of February 2007 (J. Vaidya, personalommunication).

ORT with Electronsn alternative technique, more closely aligned with the early

olor version of figure is available online.)

reast IORT studies, is in place at the European Institute of

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IORT following partial mastectomy 29

ncology (EIO) in Milan, Italy. These investigators com-enced a dose escalation study in 1999 using a high-energy

lectron source (3-9 MeV) (Liac, distributed by Info & Tech,ome, Italy). The group refers to the technique as ELIOTELectron IOrT).13 Inclusion criteria were initially age � 48,umor size � 2 cm, no EIC or DCIS, negative margins, andathologically negative nodes. In the first phase of the trial,ORT was used as a replacement for the boost dose treating7 women with 10 to 15 Gy and then post-operatively add-

ng an additional 44 to 40 Gy, respectively, of WB-XRT.nitial goals were to replicate the early tissue tolerance asemonstrated by the groups in MCO and CRLC. As patientsolerated “boost” IORT well, they then increased the dose in6 women to 17 Gy, 19 Gy, and finally 21 Gy using IORT inll as the sole method of postquadrantectomy radiotherapy.total of 70 women in the group actually received 21 Gy,

elivered to the 90% isodose, the radiobiologic equivalent of0 Gy WB-XRT.In the operating room, all patients in the EIO trial undergo

entinel node biopsy (SNB) to demonstrate absence of nodalnvolvement, followed by a quadrantectomy.14 The marginsf the surgical cavity are mobilized so that tissue edges can berought together to create the target volume. This is accom-lished by circumferentially freeing the breast tissue from theectoralis major muscle below and the skin above. This

eaves a portion of breast tissue around the surgical cavityhich is only attached in its periphery to remaining breast

issue or soft tissue surrounding the breast. Through the openncision, an aluminum–lead plate combination is then placedt the base of the surgical cavity on the exposed pectoralisajor muscle to act as a beam-stopper and to prevent back-

catter (lead and aluminum components, respectively). Thedges of the quadrantectomy cavity margins are then tempo-

Figure 2 Lumpectomy cavity margins apposed before ap

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arily drawn together with large sutures over the lead–alumi-um plate to create a target volume. The thickness of thereast tissue is then measured as the energy of the electroneam is selected based on tissue thickness. The skin is nextetracted away from the center of the open incision afterhich an appropriately sized collimator is brought over thereast tissue to be irradiated and then directed such that thelectron beam will treat a 1- to 3-cm margin of breast tissueround the edges of the surgical cavity. The collimator isnally hard-docked to the linear accelerator. After confirm-

ng that skin is not in the path of the beam, the treatment iselivered over a matter of minutes. In this way, the singleadiation dose is delivered directly to and through the targetreast tissue representing the edges of the surgical cavity, butlocked behind the breast tissue by the beam-stopper whichrevents irradiation of muscle, rib, heart, and lung. The do-imetry using this approach has been described.14 Once thereatment is complete, the sutures are cut, the beam-stoppinglate is removed, a drain is placed, and the incision closed.o further radiation treatments are given postoperatively.In a report on early results from January 2000 to February

002 with the first 237 patients (mean age, 59 years; ageange, 33-80) treated with single fraction, “full-dose” 21 Gynd a median follow-up of 19 months (7-33 months), 4 pa-ients (1.7%) developed breast fibrosis (in 1 patient severe,ut resolving in 24 months), 3 patients (1.4%) developed

psilateral breast cancer, 2 patients (1.0%) developed con-ralateral breast cancer, 1 (0.5%) patient developed supracla-icular node metastasis, and 1 patient (0.5%) developed dis-ant metastases. The group reported that only 2.5% of sideffects seen with this approach were directly attributable toORT.15 In 2005, with mean follow-up of 24 months, theroup reported updated findings on 590 patients (including

ating sutures tied. (Color version of figure is available

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he 16 patients in whom IORT was used as the boost dose). Aotal of 19 patients had developed mild breast fibrosis3.2%), and 6 patients had developed local recurrences (1%;IBTR in the tumor bed and 3 new primaries in other quad-

ants).16 Although favorable, it is too early to know whether

Figure 3 Collimator in place over lumpectomy cav

able 1A Overview of APBI Clinical Trials

hase I/II

Series [Ref] APBI Method

oswell Park IORT (ortho* collimator) 1niv College Hospital,London

IORT (ortho applicator) 2

IO/Milan IORT (electrons collimator) 2anta Chiara IORT (electrons collimator) 2enzetti IORT (electrons collimator) 2tanford IORT (ortho collimator) 1SKCC IORT (brachytherapy) 1NC IORT (in vivo) 1

hase III

IO/Milan [18] WB XRT/IORT 6niv College Hospital,London [12, 13]

WB XRT/IORT 6

rtho � orthovoltage; NR � not restricted; NS � not specified; NA � not

he IBTR rate of 1% at 24 months will remain relatively stabler rise significantly, or whether adverse reactions to the largeringle fraction of radiotherapy will appear with time. Theroup at the EIO is nearing completion of a phase III ran-omized study with single fraction breast IORT compared

gins. (Color version of figure is available online.)

RT Schedule Sites NF/U

(Mean)

0 Gy surface dose Single 7 6 yrsat margin, 5 Gy at 1 cm Multiple 22 45 mos

at 90% isodose Single 574 24 mos4 Gy at Dmax Single 47 48 mos

Single 86 NAsurface dose Single 25 36 mos0 Gy @ 1 cm Single 38 NAmin at tumor isocenter Single 10 6 mos

WB XRT vs 21 Gy IORT Single 754 NAWB XRT vs 20 Gy atin

Multiple 774 NA

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IORT following partial mastectomy 31

ith conventional WB-XRT. Descriptive information regard-ng the group’s phase III trial comparing WB XRT with IORTas been described.16 This most recent published report fromhe EIO noted that 754 patients had been randomized intohis study.17

Other institutions are evaluating single fraction IORT us-ng a technique fairly comparable to the EIO group. Clini-ians at Santa Chiari Hospital in Trento, Italy have used singleraction IORT in 47 consecutive patients from 2000 to 2002.fter resection of lesions up to 2 cm via quadrantectomy, 20y (7 patients), 22 Gy (20 patients), and 24 Gy (20 patients)oses using electrons (34 with 8 MeV and 13 with 12 MeV)ere administered to 2 to 3 cm of the cavity margins via a

echnique similar to that used at the EIO. Other selectionriteria were age � 45 years, clinical T1N0, no DCIS at pre-iminary biopsy, positive estrogen/progesterone receptors,ow to moderate grade, and negative margins. Final histologyhowed IDC in 39 patients, ILC in 6 patients, and 2 withther invasive histologies. Patients were followed for a me-ian of 48 months (range 36-63). No local recurrences haveeen seen by the investigators at this time point.18

Investigators at Renzetti Hospital in Lanciano, Italy havesed single fraction IORT with a single 21-Gy dose specifiedo the 90% isodose line in postmenopausal women with tu-ors � 2 cm in diameter. In a slight twist to the EIO ap-roach, a saline filled silicone prosthesis was used by these

nvestigators to protect underlying tissue. The authors re-orted “small edema and hardened tissue” in the early post-perative period. No local recurrences were noted in 86 pa-ients treated with follow-up at 2 years.19

ORT withrthovoltage Radiotherapy

phase I/II trial was initiated at Stanford University in De-ember 2002. This study was based on the technique out-ined by the EIO, but used an operating room in outfitted for

able 1B

Breast Procedure Age SNB or AL/SizeN

M

umpectomy NR** Yes (most) < 5 cmumpectomy > 50 Yes < 2 cm

uadrantectomy > 48 Yes < 2 cmuadrantectomy > 45 Yes < 2 cmumpectomy Post-men Yes < 2 cmumpectomy > 40 Yes < 2.5 cmide local excisior > 60 Yes < 2 cm

artial mastectomy > 55 Yes < 3 cm

uadrantectomy > 48 Yes < 2 cmumpectomy > 50 Yes < 2 cm

ORT with a ceiling-mounted, Phillips RT 250 x-ray unit.omen who appear to be good candidates for the trial are

creened with breast magnetic resonance imaging (MRI) forocal staging of the malignancy as well as to exclude multifo-al and/or multicentric disease.20 Additional inclusion crite-ia for this study are age � 40 with DCIS or IDC � 2.5 cm,nd with margins � 2 mm.21 Women with EIC, ILC, andnvolved nodes are excluded. These criteria mirror thosesed by the William Beaumont group and therefore includeshe youngest group of women treated with single-fractionORT.

For patients requiring sentinel node biopsy, technetiumulfur colloid is injected the day before or the morning ofurgery in the nuclear medicine department. On the morningf surgery, single or multiple localizing wires are placed, aseeded, using x-ray, ultrasound, or MRI guidance to brackethe lesion. SNB is performed first, although for some patientsith upper outer quadrant lesions, we prefer to perform SNB

f possible through the lumpectomy incision after the mainpecimen has been removed. Suspicion or proof of SN in-olvement precludes IORT. The lumpectomy typically in-olves removing skin over the lesion, as well as pectoral fas-ia, to minimize positive or close margins. Specimen marginsre examined carefully during surgery and frozen sectionerformed for any suspicious lesions at specimen edge. Forll wire-guided procedures, specimen radiography is per-ormed to confirm lesion removal and determine whether theesion is centered within the specimen. Additional marginsre taken as needed. The target volume is prepared by cir-umferentially approximating lumpectomy cavity marginsith sutures (Fig. 2), and a collimator is positioned over the

arget volume. The x-ray unit is swung over the OR table,ard-docked to the collimator, and IORT is delivered to 1 tocm of cavity margins using 200 kV orthovoltage radiation

s the only radiotherapy treatment (Fig. 3).The initial 3 patients in this series were treated with 15 Gy

urface dose to confirm feasibility and early tissue tolerance

TxMargin LR

G/ECosmesis Gr 3/4 Toxicity

NS 29% NA 0%� 1 cm 0% NA NA

1 to 3 cm 1.4% NA NA2 to 3 cm 0% 92% 6%NA 0% NA NA1 to 3 cm 0% NA 2%1 cm NA � 83% NA1 to 2 cm NA 67% 0%

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s suggested by prior investigators, with the remaining pa-ients treated to a total surface dose of 17 Gy. A dose of 17 Gyith orthovoltage radiotherapy is biologically comparable

o the 21 Gy total dose with electrons used by the EIO.ransient, moderate induration in the breast tissue lastingpproximately 6 months is common. Thus far, no patientas experienced a local recurrence. This includes 25 pa-ients with a minimum follow-up of 2 years (range 2 to 4.2ears follow-up).

ORT withlectrons Pre-Excision

nvestigators from University of North Carolina at Chapelill have embarked on a trial utilizing breast IORT, but withelivery of radiation to the tumor and surrounding breastissue before tumor excision. Their rationale for this approachs that tumor targeting is more accurate while the tumor isn-situ, and that the delivery of radiotherapy at this pointllows for a smaller overall volume of irradiated tissue com-ared with other forms of collimator-based, breast IORT.The trial is designed to include women � 55 years of age,

ith unifocal IDC determined by core biopsy, lesion seen onltrasound, T � 3 cm, and clinically negative nodes. Womenith ILC and pure DCIS have been excluded. Women with

nvolved nodes were initially excluded, but later permitted.On the day of surgery, the patient’s lesion is imaged with

ltrasound, and the relationship of the lesion to the skin,uscle, and lung measured, while an optimal angle for breast

ORT is determined. At this point, the cone size needed toover the tumor plus a 1.5- to 2-cm margin is selected, andhe electron energy selected that would provide a minimum5 Gy to the tumor isocenter, 90% isodose at a depth 1 cmosterior to the tumor, with a 10 Gy maximum dose to theleural/chest wall interface. In the operating room, a percu-aneous guidewire is placed into the breast under sterile con-itions to localize the cancer, then SNB �/� frozen section iserformed. Next, a 6- to 7-cm incision made over the tumor,kin flaps are mobilized for a distance of 2 to 3 cm circum-erentially, then skin edges retracted to allow room for colli-

ator placement. IORT is then delivered using the MobetronIntraOp Medical, Inc., Santa Clara, CA) using 9- or 12-MeVlectrons through collimator sizes of 5 or 6 cm. The tumor ishen excised with the goal of achieving a minimum 1 mmumor-free margin.

Mean follow-up for this study is 6 months. Of the 18atients treated with breast IORT in this series, 10 receivedingle fraction treatment as their only form of radiotherapy.f the remaining 8 patients, 5 went on to receive additional

adiotherapy and 3 had mastectomy for a variety of reasons,ncluding positive margins or other histologic findings thatid not meet inclusion/exclusion criteria.

ORT with Intracavitaryigh-Dose-Rate Brachytherapy

t Memorial Sloan Kettering Cancer Center (MSKCC) intra-

perative, high-dose-rate (HDR) brachy therapy has been

tilized to deliver APBI. Women are offered trial participa-ion if age is � 60, T � 2 cm, and lymph nodes are clinicallyegative. After SNB and partial mastectomy with wide localxcision, the partial mastectomy specimen is submitted forpecimen radiography to determine orientation of the malig-ancy within the specimen as best possible. The specimen ishen analyzed by surgical pathologists who also assess mar-ins for tumor and perform touch prep as appropriate. Ad-itional margins are taken as needed. A rectangular silasticpplicator (H.A.M. silastic applicator; Mick Radio-Nuclearnstruments, Inc., Mount Vernon, NY) with parallel channelss inserted into the lumpectomy cavity with applicator size/hannel number varying for each patient to ensure the bestatch possible between cavity size and applicator. If there is

ny space between breast tissue and applicator margins, aurse string suture is placed through the breast tissue topproximate breast tissue to the applicator edge. The appli-ator is connected to an HDR afterloader using 192Ir. A pre-cribed dose of 20 Gy at 1 cm from applicator surface wassed initially, with this dose since lowered to 18 Gy. Radio-herapy is delivered with the benefit of computerized treat-ent planning to optimize dose homogeneity through mod-lation of dwell times of the 192Ir source within thepplicator. Dosimetry is calculated with the 20-Gy dose pre-cribed at 1 cm from the surface of the applicator. Dwellimes are calculated by computer and then remote afterload-ng is accomplished after personnel have left the operatingoom. The MSKCC group has reported encouraging resultsrom the first 38 patients treated in this series (Table 1).22

ummarymerging data suggest that APBI using single fraction IORT ispromising alternative to conventional whole breast radio-

herapy for select women with early-stage breast cancer.ith IORT phase III clinical trials are testing current initial,

autious selection criteria, as well as long-term safety andffectiveness of this approach. Ongoing phase I/II trials couldead to broader patient selection criteria, refinement of exist-ng techniques. Future studies could introduce new deviceso deliver this particular form of APBI.

cknowledgmentngoing investigation with APBI performed at Stanford is

unded in part by generous gifts from the Vadasz Familyoundation, the Northern California Chinese Unit of themerican Cancer Society, as well as the Chung-Sie Hsiaound.

eferences1. Landis D, Luo W, Song J, et al: Variability among breast radiation

oncologists in delineation of the postsurgical lumpectomy cavity. Int JRadiat Oncol Biol Physz: Int J Radiat Oncol Biol Phys 67:1299-1308,2007

2. Garcia-Barros M, Paris F, Cordon-Cardo C, et al: Tumor response toradiotherapy regulated by endothelial cell apoptosis. Science 300:1155-1159, 2003

3. Bartelink H: Commentary on the paper “A preliminary report of intra-

operative radiotherapy (IORT) in limited-stage breast cancers that are

1

1

1

1

1

1

1

1

1

1

2

2

2

IORT following partial mastectomy 33

conservatively treated.” A critical review of an innovative approach. EurJ Cancer 37:2143-2146, 2001

4. Cuncins-Hearn A, Saunders C, Walsh D, et al: A systematic review ofintraoperative radiotherapy in early breast cancer. Breast Cancer ResTreat 85:271-280, 2004

5. King TA, Bolton JS, Kuske RR, et al: Long term results of wide fieldbrachytherapy as the sole method of radiation after segmental mastec-tomy for Tis, T1, T2 breast cancer. Am J Surg 180:299-304, 2000

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