Chapter

Breast IMRT

Douglas W. Arthur, Monica M. Morris,Frank A. Vicini, Nesrin Dogan

7

Contents

7.1 The Clinical Problem . . . . . . . . . . . . . . . . . . . 3717.1.1 Isolated Breast Treatment . . . . . . . . . . . . 3717.1.2 Loco-Regional Breast|Chest Wall Treatment . . 3727.1.3 Simultaneous Integrated Boost (SIB) . . . . . . 373

7.2 Unique Anatomical Challenges . . . . . . . . . . . . . 3737.2.1 Lung and Heart Avoidance . . . . . . . . . . . . 3737.2.2 Inter- and Intra-Fraction Motion . . . . . . . . 374

7.3 Breast Volume Delineation . . . . . . . . . . . . . . . 375

7.4 Planning and Dose Prescriptions . . . . . . . . . . . . 3757.4.1 Isolated Breast . . . . . . . . . . . . . . . . . . 3757.4.2 Loco-Regional Breast|Chest Wall IMRT . . . . 376

7.5 Clinical Experience . . . . . . . . . . . . . . . . . . . . 3777.5.1 Isolated Breast IMRT . . . . . . . . . . . . . . . 3777.5.2 Loco-Regional Breast|Chest Wall IMRT . . . . 379

7.6 Future Directions|Conclusion . . . . . . . . . . . . . . 379

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

7.1 The Clinical Problem

The radiation oncologist is involved in the managementof breast cancer patients throughout the spectrum ofthe disease: from adjuvant treatment of early and locallyadvanced stage to palliative treatment of metastasis. Inthe adjuvant setting there are two distinct clinical situ-ations; (1) treatment of the breast only following breastconserving surgery for early stage disease and (2) treat-ment to the breast|chest wall and regional nodes forlocally advanced disease. The use of radiotherapy inthese clinical settings has been shown to improve local,local-regional control and overall survival [1–4]. Whenradiotherapy was first introduced into these clinical set-tings, broad field designs were used. These originalbroad fields were simplistic in design, and limited bythe planning and treatment delivery systems available.However, because of their simplicity, success in reducingdisease recurrence, and ease of implementation, thesetreatment techniquesquicklybecamewidelyadopted. Infact, themajorityof treatment centers todaycontinue the

same general disease management principles and treat-ment approaches originally designed and practiced inthe 1970s and 1980s. Although upgraded field matchingtechniques and CT based treatment planning have beenincorporated in many centers, minimal modificationshave been made until recently with the emergence of im-age based treatment planning and advanced, intensitymodulated radiotherapy delivery techniques. IntensityModulated Radiotherapy (IMRT) in the treatment ofbreast cancer offers improved dose conformality andhomogeneity. Only through appropriate investigationwill we be able to determine whether this improvementin dose delivery actually translates into a clinical ben-efit and, therefore, justify widespread adoption of thistreatment technology.

7.1.1 Isolated Breast Treatment

Treatment of the whole breast following lumpectomy toachieve in-breast disease control has been documentedto be successful in both local control and cosmetic out-come [1, 2, 5]. The use of parallel opposed tangentialfields, with varying levels of mechanical compensa-tion, has become the standard whole-breast treatmentapproach due to its straight-forward simplicity, and fa-miliarity of use from large randomized trials. The needfor improvements in these simplebut effective treatmentapproaches has been challenged and, therefore, it is ap-propriate to evaluate what improvements can be realizedwith IMRT [6–8]. As local control rates are primarily de-pendent on appropriate surgical resection followed bymodest doses of adjuvant radiotherapy, improved dosecoverage of the breast target or dose escalation for tu-mor control may not be necessary. It has been suggestedthat the application of IMRT forces physicians to fo-cus attention on target delineation and target coveragetherefore possibly yielding an improvement in diseasecontrol [9]. However, this advantage would not be a re-sult of treatment delivered with IMRT technology butrather a result of the target-focused planning processwhich can also be achieved through appropriate applica-tion of conventional treatment techniques.Thepotential

372 III. Clinical

advantages that IMRT technique may have over conven-tional 3D and non-3D techniques are (1) the ability toachieve dose uniformity throughout the breast targetand (2) the potential to reduce the dose to underlyingheart and lung. These abilities are expected to trans-late into an improved cosmetic outcome and reducedtoxicity.

Although it is recognized that, in many women, ap-propriate use of mechanical wedges produces acceptablehomogeneity, management of moist desquamation inthe inframammary fold and low axilla is often nec-essary and late breast fibrosis (inframammary foldfibrosis), breast edema and costochondral discomfortare frequently encountered. Possibly due to the ease ofstandard tangential treatment, the successful local con-trol rates and the significant improvement of life qualityover mastectomy, these toxicities have been acceptedas a part of the standard of care. Initially, it was com-mon to follow the treatment guidelines used in NSABPB-06, where uncompensated tangential fields (i. e., nowedge filters used) were prescribed to midplane at apoint two-thirds the distance from the skin to the baseof the tangent at central axis [10]. As a result, the ante-rior aspect of the treated breast received a daily dose andtotal dose that exceeded the prescription dose, maskingthe fact that doses higher than 50 Gy to the surgicalbed were often delivered. The degree of this inhomo-geneity would have been variable as it is dependenton the size and shape of the breast. In the absence ofdosimetric information, the effect is difficult to quan-titate. Recognizing the varying level of inhomogeneitywith such an approach, wedge filters have since beenuniversally adopted to compensate for the differencein breast width encountered. However, wedges do notcompensate for three-dimensional changes and toxic-ity related to dose inhomogeneity is still encountered.Mechanical lead compensators have been described asa method of providing customized compensation thatachieves a highly homogeneous dose distribution [11].This approach has been adopted in some centers but hasnever achieved widespread use as planning, compen-sator construction and treatment delivery times havebeen viewed as excessive, despite dosimetric benefits.The emergence of IMRT and multi-leaf collimation hasprovided an electronic method of 3D compensation thataddresses these difficulties by providing an automatedmethod of delivering a homogeneous dose. For thisand other reasons, IMRT has the potential to becomethe preferred method of radiation delivery for breastcancer.

In the treatment of breast-only, IMRT is unlikely tomake a great improvement in the already-low normaltissue complication probability. In whatever manner thebreast target is defined, it remains a concave structurewith lung and, if left sided, heart tissue directly adja-cent. Avoiding dose to the underlying lung and hearthas been the goal of some IMRT techniques; however,

the dose reductions are marginal and of questionableclinical benefit when standard tangential field arrange-ments are used [12]. Creative multi-field arrangementshave also been attempted, but the added complexity andassociated increase in integral dose without the obviouspotential for clinical benefit has prevented acceptanceinto clinical use [13–15]. The proper design of standardbreast-only tangential fields limits the dose delivered tothe heart and ipsilateral lung to an acceptable level inthe majority of women. Although patients are encoun-tered that present with a unique chest wall shape leadingto an excessive amount of lung and|or heart in the field,these rare cases can usually be managed with minimalchanges in tangential beam entry angle or the additionof a small heart block that reduces dose to these criti-cal structures. Alternative methods of reducing the doseto neighboring lung and heart have been studied, butnot yet widely accepted and include field arrangementsand controlled breath hold techniques [16–18]. Reviewof the late heart and lung clinical toxicity data followingtreatment with standard tangential fields supports theidea that further reduction of dose to the heart and lungbeyond that achieved with standard tangential field isnot necessary [19–21]. Therefore, the benefits of IMRTin isolated breast treatment should be focused on deliv-ering a homogeneous dose distribution throughout thebreast in a population of patients with varying breastsize and shape with the promise of reducing acute andlate soft tissue toxicity.

7.1.2 Loco-Regional Breast|Chest Wall Treatment

Despite limited publications on use of IMRT in the set-ting of breast|chest wall and regional lymphatics, it is inthis clinical setting of locally advanced disease that thereis a real potential role for IMRT due to the undeniableneed for improvement in the ability to achieve dose cov-erage of target with maximal normal tissue avoidance.The comprehensive coverage of the breast, chest wall,supraclavicular nodes, internal mammary nodes, andpossibly the axilla presents a complicated target volumethat wraps around the immediately adjacent lung, heart,mediastinum and brachial plexus. Many conventionaltechniques have been devised and investigated for local-regional coverage inboth the settingsof intactbreast andpost-mastectomy treatment [22, 23]. Although many ofthese techniques offer improved dosimetric coverage ofthis complex target volume and a reduction in normaltissue exposure, the partially wide tangent techniqueoffers the best balance between target coverage andreduction in heart and lung dose [24]. However, it isrecognized that there is no universally successful tech-nique in a population presenting with widely varyingthoracic structure and breast dimensions. One of themore obvious concerns with the inclusion of the inter-nal mammary nodes is the resultant increase in dose

373Douglas W. Arthur, Monica M. Morris, Frank A. Vicini, Nesrin Dogan Chapter 7 Breast IMRT

received by the heart. This concern is augmented withthe knowledge that most of these patients will receivecardiotoxic agents as a part of their chemotherapy regi-men and further validates the role of IMRT if techniquesare shown to reduce cardiac dose.

7.1.3 Simultaneous Integrated Boost (SIB)

Several studies have indicated that delivering a boostdose to the tumor bed plus margin, typically with elec-trons, following conventional whole breast radiotherapyresults in improved in-breast control rates [25, 26]. De-spite the documented local control benefit, the design ofthese boost fields in many practices remains a clinicalprocess based on mammograms, clinical exam and siteof surgery. CT-based planning has opened the eyes ofradiation oncologists, revealing the potential for boostfield design error if image guidance is not incorporatedinto the boost field planning process. With the advancedplanning process of IMRT, there emerges the potentialfor incorporating the boost dose into the whole breastdose delivery, therefore simultaneously delivering theboost dose – simultaneous integrated boost, SIB. Thiswould facilitate shortening the treatment course deliv-ery timebyone to twoweekswhilepotentially improvingthe conformance of the boost dose to the boost target.Minimal investigational work has been completed inthis area, possibly related to the high rates of local con-trol seen with present boosting techniques and becauseshortening the treatment course to five to five-and-a-half weeks is not remarkable compared to achievementswith newer techniques accelerating the overall treat-ment course further and completing in three- and-a-halfweeks or even in five days [27, 28]. It is uncertain atthis time whether SIB can be incorporated into stan-dard practice and further investigation is needed toaddress several questions. These questions include thedesign of reliable field arrangements that would allowSIB dose delivery and avoid increase dose delivery tosurrounding normal tissue and critical organs. SIB isbased on the ability to deliver an incremental daily doseincrease to the boost target while continuing deliveryof standard doses to the remainder of the breast. Theamount of dose increase that will result in equivalent tu-mor control and breast tissue toxicity rates experiencedwith present techniques has not yet been determined.Lastly, additional daily treatment time will be requiredto deliver this treatment approach. Whether the benefitof applying IMRT technology in this situation justifiesthe additional time needed to plan and deliver treat-ment with a SIB is unknown and requires additionalinvestigation.

An example of early investigation into the use of SIBwith whole breast irradiation is described by Singla et al.[29]. They investigated the feasibility of SIB-IMRT fortreatmentof tenearly stage left-sided invasivebreast car-

cinomapatients.Theycompared target volumecoverageand normal tissue dose using SIB-IMRT using six-fieldnon-coplanar fields to traditional tangential fields op-timized with wedges or compensating filters with anen-face electron lumpectomy bed boost. Their resultsshowed that there was no difference seen in the cover-age of left breast and lumpectomy bed using SIB-IMRTvs conventional 3D CRT. However, the plans generatedwith SIB-IMRT were significantly more conformal thanall other plans. Their study also showed that SIB-IMRTsignificantly reduced the maximum dose to the left lungby ∼22%. However, this benefit came at the expense ofincreased left breast dose outside of the lumpectomybed, a direct result of the simultaneous boost. Theyconcluded that although the use of a simultaneous in-tegrated boost to the lumpectomy bed seems feasible,the clinical consequences of the increased ipsilateralbreast dose remains unknown and therefore should beinvestigated further.

7.2 Unique Anatomical Challenges

7.2.1 Lung and Heart Avoidance

As modern treatment techniques allow us the luxury ofworking not only for a five-year cure in breast cancer,but also an avoidance of premature death [30], the tox-icity of treatment becomes an increasingly importantconsideration. In breast cancer, early techniques, suchas the hockey stick approach, were effective, though theimprovement in survival was offset by excess treatment-related cardiac morbidity. More modern techniques(tangents) continue to demonstrate an improved diseasecontrol with acceptable normal tissue toxicity [19–21].The goal of IMRT is to decrease further treatment toxi-city while concurrently maintaining early stage diseasecontrol and|or increasing locally advanced disease con-trol.

Current standard treatment techniques typically en-tail full-dose treatment to at least 10–15% ipsilaterallung volume and 3–6% of the heart volume for breast-only tangents [31, 32]. Greater treated volumes on theorder of 15–25% for lung and 10–25% for heart canbe expected for treatment involving the regional nodes(internal mammary chain, supraclavicular fossa, axilla).Marks et al. have attempted to quantify lung injury afterradiotherapy using SPECT imaging [33]. They demon-strated that for most patients there was a statisticallysignificant, dose-dependent reduction in regional bloodflow at all time points following pulmonary irradiation,developing within three to six months post therapy atdoses above 5–10 Gy. Such treatment has a reportedclinical pneumonitis rate of between 1 and 4% [34].

374 III. Clinical

Similar studies with regard to cardiac injury after radio-therapy demonstrate dose-dependent cardiac perfusiondefects in 60% of patients at six months [35, 36]. Pre-liminary findings indicate that patients with cardiacperfusion defects shortly after therapy are more likelyto experience transient chest pain in the two years fol-lowing [37]. The long-term, clinically relevant effects ofsuch changes are unknown. Geynes et al. noted that theearly randomized trials in breast cancer which demon-strated excess cardiac morbidity also utilized treatmenttechniques likely to deliver at least 25 Gy to 25% or moreof the cardiac volume; whereas modern techniques typ-ically deliver this dose to 5–12% [31]. This same groupanalyzed the cardiac and myocardial DVHs for tan-gential therapy in left-sided stage I breast cancer andestimated the mean excess cardiac risk at 2% using arelative seriality model; however, there remained pa-tients whose excess risk was as high as 9–12%, for whomintensity modulated radiotherapy was suggested [37].

As mentioned above, breast-only tangent radiother-apy is associated with a quite low but real risk ofpneumonitis and cardiac disease. A number of studiesof isolated breast IMRT have consistently demonstratedimproved target volume dose homogeneity, a modestimprovement in normal tissue sparing, with an asso-ciated increase in the mean doses to the contralateralbreast and lung [14, 38, 39]. Isolated breast IMRT hasbeen successfully implemented in the clinic with ex-cellent cosmetic and acute complication results [39];however, it will take lengthy follow-up of many morepatients thus treated to demonstrate any incrementalimprovement in an already-low toxicity profile.

As opposed to simple tangents, the use of IMRT inthe setting of locally advanced disease, with treatmentof the regional nodes, may prove to be more compellingand will certainly be more technically challenging. Con-siderably fewer studies have been done in this setting,and all are planning studies. The lack of clinical use ofIMRT for local-regional breast cancer treatment likelyrelates to concerns about set-up accuracy, organ motionand increased integral dose. Increased integral dose, asis consistently demonstrated in IMRT planning studies,may be associated with a near-doubling of the inducedmalignancy rate [40]. While the risk of second malig-nancy with radiotherapy is so low as to be statisticallyinsignificant 15 years post-therapy, it does remain areal consideration, particularly amongst our youngerpatients [41, 42].

Kreuger et al. conducted a planning study of chestwall and regional nodal IMRT with the CTs of ten post-mastectomy patients with left sided stage II–III breastcancer [43]. They demonstrated increased dose unifor-mity with minimum doses to chest wall and internalmammary chain improved from 31 and 22 Gy to 44 and43 Gy, respectively. Cardiac normal tissue complicationprobability (NTCP) was unchanged with IMRT, while ip-silateral lung NTCP was decreased. However, the mean

Table 1. Conservative normal tissue constraints presently appliedat VCU

Normal tissue Dose limit

Ipsilateral lung < 5 Gy to < 30% of lung< 20 Gy to < 10% of lung0 Gy to < 50% of lung

Contralateral lung 0 Gy to 100% of lung

Heart < 5 Gy to < 50% of total heart volume< 10 Gy to < 33% of total heart volume< 20 Gy to < 10% of total heart volume40 Gy to < 3% of total heart volume

dose to contralateral lung and breast increased. Johans-son et al. present similar findings in their planning studyof standard photons, IMRT and proton therapy for nodepositive left-sided breast cancer treatment [44]. In thisstudy, mean NTCP for heart decreased from 7% withstandard tangents to 2% and to 0.5% with IMRT andprotons, respectively. NTCP for the left lung remained28% for both tangents and IMRT and decreased to 0.6%for protons.

Most of the data used to set lung and heart doseconstraints is generated from patients treated for lungcancer and other malignancies where the disease pro-cess frequently outpaces the development of late normaltissue toxicity. Therefore, when treating young patients,setting definitive normal tissue constraints is difficultas the late effects of treating large volumes of normaltissue to low doses are not known. When constraintsare set, they tend to be conservative, see Table 1, whichoften becomes restrictive and may limit or potentiallyinhibit the ability of the IMRT planning process toachieve the desired dose conformality. Until additionaldata is available, a reasonable approach to setting nor-mal tissue constraints and determining cost functionsis to use normal tissue dose tolerances derived fromdata observed in other organ sites or to use clinicallyacceptable dose|volume data generated from standardplans|techniques that have resulted in acceptable ratesof local control and complications.

7.2.2 Inter- and Intra-Fraction Motion

With the generous tangential fields and target def-inition used with breast-only treatment, inter- andintra-fraction motion is not a significant factor. It is as-sumed that any movement of the true target, which lieswithin the confines of the breast tissue, moves withinthe fields as defined by the previously discussed con-ventional methods. However, that assumption cannotbe extrapolated to local-regional treatment. The inter-nal mammary lymph nodes are located in immediateproximity to the lung and heart and the dose is tightlyconformed to the target structure in order to minimizenormal tissue dose and avoid toxicity. Because of the

375Douglas W. Arthur, Monica M. Morris, Frank A. Vicini, Nesrin Dogan Chapter 7 Breast IMRT

sharp dose fall-off at the field edge and the tight confor-mality of dose, intra-fraction movement, as a result ofbreathing, may be a factor confounding accurate dosedelivery. Studies exploring this potential pitfall indicatethat normal breathing motion results in approximately5 mm of position change and that this movement has lit-tle effect on dose homogeneity within the clinical targetvolume (CTV) [45, 46]. Fraction to fraction differencescan be seen; however, due to the interplay between respi-ratory motion and multi-leaf collimator motion duringtreatment delivery. Over a full course of treatment, how-ever, there are no statistical differences between theplanned and expected dose distributions. An effect ofbreathing motion that may require attention when treat-ing a local-regional target is the resultant degradationof the planning target volume (PTV) dose uniformitythat requires an increase in CTV to PTV expansion[45]. In addition, lung and heart doses also increase.Breath-hold, respiratory gating and 4D techniques canlimit motion effect and remove the need for additionalCTV-PTV expansion.

7.3 Breast Volume Delineation

In keeping with the IMRT planning principles used inother treatment sites, the planning of breast-only IMRTbegins with the accurate delineation of target and crit-ical normal tissue volumes. In breast-only treatment,conformal coverage of the breast immediately becomesproblematic because of the inability to reliably definethe extent of breast tissue and, therefore the target, to betreated. Many publications discussing IMRT for breastcancer simply state that the breast volume was enteredfor planning, and the volumes depicted in publicationvary widely. However, in reality breast tissue extent can-not be reliably defined on CT scan and therefore thisprocess translates into the entry of a breast target con-tour that is manually delineated relying on knowledgeof breast anatomy, external skin contour and often ex-ternal markers that are placed prior to CT to delineatebreast tissue extent based on palpation. This approachresults in the uncomfortable situation of planning thedelivery of a highly conformal treatment to a target thatis subjectively delineated. One solution has been to rec-ognize that treatment using standard tangential fieldshas historically resulted in excellent local control, andso to assume that the clinical methods of defining thesefields reliably covers the target and, therefore, can alsobe used to define the target for IMRT. As a result of thisthinking, many of the various published IMRT tech-niques define the breast tissue by designating all tissuewithin standard tangential fields, excluding lung, as thebreast target. Others have developed dose optimizationapproaches that simply assure dose uniformity to alltissue within the tangential fields.

7.4 Planning and Dose Prescriptions

7.4.1 Isolated Breast

Although it is recognized that there are physicians whoprefer to have the breast volume contour entered free-hand on each CT cut, at the Virginia CommonwealthUniversity we have found that the contouring of thetarget volume is efficient and consistent when the con-tour is automated and guided by standard tangentialfield borders. Using tangential field borders, designedwith clinical and CT guidance, the planning systemcan be programmed to auto-contour the target by in-cluding all tissue within the tangential field bordersexcluding lung. Although the chest wall is includedwithin the breast reference volume, this has little impacton the final dose distribution due to the effect of thelung|chest wall interface on the final dose distribution.We additionally retract the contour 5 mm from the skinsurface to account for dose build up. The IMRT plansare generated to be delivered with the step-and-shoottechnique that employs the segmented multi leaf colli-mator (sMLC). All treatments are planned using 6-MVphotonbeams.The inverseplanningoptimization isper-formed using the Pinnacle [3] planning system (Philipslaboratories,Milpitas,CA).Apencil beamcalculational-gorithm is used during optimization and the final doseis calculated, with heterogeneity corrections, using asuperposition|convolution algorithm after the leaf se-quencing isdetermined.Thedosimetric goal for isolatedbreast IMRT is to achieve 95% target volume coveragewith 100% of the prescription dose. Lung and heartvolumes are not considered when optimizing the dosedistribution as it is assumed that the volumes included

Fig. 1. Isolated breast treatment – dosimetric comparison of IMRTand Wedge only dosimetry

376 III. Clinical

Fig. 2. Breast volume dose volume histogram

reflect the acceptable volumes included in standard tan-gential fields based on the methods used for breast targetvolume delineation.

Treating with standard tangential fields, wherewedges are the only form of tissue compensation used,often results in significant areas inhomogeneity that aretypically 10–15% greater than the prescribed dose. Thedegree of inhomogeneity is dependant on breast sizeand shape. Acute and late breast and overlying skintoxicity are typically experienced, most commonly inthe infra-mammary fold. These normal tissue effectsmanifest as moist desquamation with subsequent riskof telangiectasia and|or degree of fibrosis. With IMRTplanning and dose delivery these areas of increased dosecan be reduced with a correlative improvement in toxi-city. Figures 1 and 2 illustrate the improvements in dosedistribution that can be achieved with IMRT planningas compared with results from standard planning usingwedge compensation.

7.4.2 Loco-Regional Breast|Chest Wall IMRT

Treating the breast|chest wall and nodal regions as acontiguous volume with an IMRT planned and deliv-ered approach, constructed for dose conformality withthe generation of sharp dose gradients to protect organsat risk, has not yet been adopted into routine clinicaluse. An acceptable method of approaching this treat-ment challenge has not yet been devised. Remouchampset al. have presented improvements in internal mam-mary node coverage with reduction in dose to lung andheart through their methods of moderate Deep Inspi-ration Breath Hold combined with IMRT [17, 18]. Theform of IMRT described delivers a homogeneous dosewith a standard tangential field arrangement. In this ap-proach, dose conformality constructed to avoid organsat risk is not applied, but rather, the improvement indose delivery achieved by optimizing the geometric po-sitioning between the target and the organs at risk byutilizing the breath hold technique.

The spatial relationship between the loco-regionaltarget and the underlying lung and heart is challengingand presently described approaches either compromise

Fig. 3. Isodose comparison between field arrangements for loco-regional coverage – supraclavicular target shaded purple – breastand internal mammary node target shaded red

on target coverage or accept an increase in dose tonormal structures. In our preliminary investigation, wehave evaluated a two-field 3D-CRT, and a two-, six- andnine-field IMRT approach and compared dose distribu-tions as they relate to loco-regional target coverage andnormal tissue avoidance. Initially, we set conservativenormal tissue constraints, Table 1. Plans covering thebreast and internal mammary nodes (IMN) were gener-ated and optimized with the goal of covering 95% of the

Fig. 4. Total lung dose volume histogram – technique comparison(black circles signify lung volume constraint goals)

377Douglas W. Arthur, Monica M. Morris, Frank A. Vicini, Nesrin Dogan Chapter 7 Breast IMRT

Fig. 5. Heart dose volume histogram – technique comparison(black circles signify lung volume constraint goals)

breast target volume with 100% of the prescribed dose.A two-field tangential 3D-conformal plan was comparedto a two-field IMRT plan, a six-field non-coplanar beamIMRT plan, and an IMRT plan using nine equally spacedcoplanarbeams.Thegantryanglesused for the six-beamarrangement were designed such that the sparing of or-gans at risk was maximized and fields were positionedat angles of 305, 125, 325, 145, 105, and 345◦. Plans wereoptimized for breast target coverage and normal tissueavoidance. Single CT cut dose distribution comparisonof these four-field arrangements is depicted in Fig. 3.The spatial relationship between the loco-regional tar-get and critical organ structures changes from superiorto inferior and therefore a three-dimensional dose com-

Table 2. Dose received by percent lung volume

Goal dose to% lung vol

Actual lung volume receiving dose

Control3DCRT

2 Fld 6 Fld 9 FldIMRT IMRT IMRT

V1 Gy< 50%

35 22 39 97

V5 Gy< 30%

18 9 14 23

V20 Gy< 10%

13 5 6 5

Table 3. Dose received by percent heart volume

Goal dose to% heart vol

Actual heart volume receiving dose

Control3DCRT

2 Fld 6 Fld 9 FldIMRT IMRT IMRT

V5 Gy < 50% 10 5 29 32

V10 Gy < 33% 6 3 4 4

V20 Gy < 10% 4 2 2 1

V40 Gy < 3% 1 0 0 0

Table 4. Internal mammary node (IMN) dose coverage

IMN volumecoveredby the % of theprescriptiondose

Treatment technique

Control3DCRT(%)

2 Fld 6 Fld 9 FldIMRT IMRT IMRT(%) (%) (%)

V100% (50 Gy) 71 85 0 34

V95% (47.5 Gy) 80 98 22 50

V90% (45 Gy) 91 99 80 67

V80% (40 Gy) 95 100 100 91

parison is needed to understand fully the differencesbetween treatment approaches. The Dose Volume His-tograms comparing the four techniques for both lungand heart are seen in Figures 4 and 5. Note that all treatwithin a range that is acceptable by known criteria. Thedose received by percent of organ at risk for the evalu-ated techniques is displayed in tabular format in Tables2 and 3 and the ability of each technique to cover theIMN target volume detailed in Table 4. This preliminarystudy suggests that the best balance between target cov-erage, as signified by internal mammary node coverageand normal tissue avoidance, appears to be achievedwith a two-field IMRT approach.

7.5 Clinical Experience

7.5.1 Isolated Breast IMRT

Many institutions have investigated breast-only IMRTwith the goal of improving dose homogeneity. Themajority of publications are dosimetric studies, withrare clinical experiences reported. All studies reportimproved homogeneity of dose throughout the breasttarget with IMRT techniques as compared to standardwedged tangential fields. Most investigators report tech-niques using standard tangential field arrangementswith differences existing in the methodology used todefine the treatment target, to obtain the desired dosedistribution, and to deliver the planned dose. Inverseplanning and various forms of forward planning havebeen used to generate homogeneous treatment plansthat can be delivered with mechanical compensators,with computer controlled multi-leaf collimation (MLC)utilizing multiple static fields, or with dynamic IMRTtreatment delivery.

Three institutions have described IMRT techniquesthat incorporatemultiple staticfieldsdelivering lowdoseto enhance the dose homogeneity of standard wedgedtangential fields [47–49]. Starting with the majority ofthe dose delivered with fields optimized with wedges

378 III. Clinical

only, Zackrisson et al. and Lo et al. fashioned additionalfields which deliver a portion of the dose to the targetexcluding the higher dose regions [48, 49]. These addi-tional fields were created with a 3D treatment planningsystem through an iterative process. Similarly, Evanset al. began the treatment delivery design with wedgedfields and augmented the dose delivery with a set oflow-dose shaped fields based on thickness maps ob-tained with an electronic portal imaging device [47]. Allthree studies demonstrated a reduction of the high doseregions within the breast. Chang et al. evaluated eightdifferent intensity modulated approaches using anthro-pomorphic phantoms and compared dose homogeneity,contra-lateral breast dose and treatment delivery time[50]. They have concluded that superior dose unifor-mity is achieved when treatments are generated by doseoptimization algorithm and delivered via the compen-sator and MLC techniques. They have also reported thatthe contralateral breast dose is maximally reduced withcollimator generated techniques, i. e. MLC or virtualwedge. However, the MLC technique requires the longesttreatment irradiation time.

With several publications demonstrating improveddose uniformity with IMRT, the importance of reduc-ing treatment planning and delivery time becomes anissue if the use of IMRT for breast cancer is to be prac-tical enough to be used in a busy clinic. This conversionto a practical, time efficient approach is exemplified inthe publications from Memorial Sloan Kettering Can-cer Center. Hong et al., initially presented a dosimetricstudy of five patients with right and five patients withleft breast involvement [12]. They presented an inverseplanning IMRT technique utilizing set target and crit-ical organ optimization criteria and compared this tostandard wedged tangential fields. They reported animprovement in dose homogeneity, with an 8% dosereduction in the superior and inferior aspects of thebreast target and 4% in the medial and lateral, as wellas a reduction in the dose delivered to the coronaryartery region, ipsilateral lung and contra-lateral breast.Although improvements in normal tissue doses and tar-get dose homogeneity were evident, the concern wasraised that these improvements may not be on a largeenough scale to justify the huge increase in planning ef-fort required for such inverse methods. In response tothis report, a simplified and efficient IMRT techniquefor the breast, referred to as simplified IMRT (sIMRT),was developed [51]. The standard tangential beam ar-rangement was used and contours, except the automatedexternal contour, were eliminated. The PTV was definedas all tissue within the tangential fields, less 5 mm beampenumbra and 5 mm from skin. For each field, a pen-cil beam grid was created and the optimal intensity ofeach pencil beam determined as proportional to the in-verse of the midpoint dose from an open beam. Theintensity distribution was then converted to a deliv-erable plan utilizing multi-leaf collimation. In fifteen

patients the sIMRT planning technique was comparedto the standard wedged pair tangential field techniqueand volume based IMRT technique (vIMRT). They re-ported that the target dose homogeneity and normaltissue dose limitation was equivalent between sIMRTand vIMRT planning. However, the planning time forsIMRT was significantly less than that for vIMRT andequivalent to the planning time for standard wedgedfields, thus converting the planning technique to onewhich can be adopted in clinics treating high volumesof patients.

Similarly, two additional methods have been de-scribed, both delivering the majority of the intendeddose with open fields and supplementing with shapedlow dose fields to optimize dose homogeneity through-out the field. The technique first described by vanAsselen et al., delivers approximately 88% of the dosewith open fields [52]. The remaining dose is given withmultiple shaped fields, or segments, that are obtainedfrom an equivalent path length map of the irradiatedvolume. Kestin et al. has described a similar technique,developed at the William Beaumont Hospital, wheremulti-leaf segments are designed based upon isodosesurfaces that result from an open set of tangent fields,with each segment weight-optimized using a comput-erized algorithm [53]. Limitations are placed on thevolume of tissue that can exceed the prescription anda set of rules is then used to derive a sequence offield apertures, with the weights of these apertures thefree parameters in the optimization. This approach isreferred to as “limited parameter set” optimization, be-cause the number of free parameters is small comparedto pixel-based, or fluence map optimizations. Othershave referred to this as aperture-based inverse planning,or segmental IMRT (sIMRT). This approach (an opti-mized combination of open fields and customized fieldapertures) allows one to compensate precisely for thechanging breast contour. With treatment planning andtreatment delivery times reported as less than 60 minand 10 min, respectively, we now have the tools toachieve superior dose homogeneity in a time efficientmanner [39].

Limited data is available regarding any clinical expe-rience with IMRT-based treatment of breast cancer. Thelargest clinical experience with whole-breast IMRT wasrecently published by the William Beaumont Hospitalgroup [39]. Two hundred and eighty one patients, withearly stage breast cancer and electing breast conserv-ing therapy, received whole breast radiotherapy afterlumpectomy using an sIMRT technique. The technicaland practical aspects of implementing this techniqueon a large scale in the clinic were analyzed, as well asthe acute toxicity and cosmetic outcome of the patients.Treatment time was equivalent to conventional wedged-tangent treatment techniques. The median volume ofbreast receiving 105% and 110% of the prescribed dosewas 11% (range 0–68%) and 0% (range 0–39%), re-

379Douglas W. Arthur, Monica M. Morris, Frank A. Vicini, Nesrin Dogan Chapter 7 Breast IMRT

spectively. No or mild acute skin toxicity was noted in56%ofpatients. Forty threepercent experiencedmoder-ate, grade II, acute skin toxicity, and only three patients(1%) had significant, grade III toxicity. Cosmetic resultat year one in the 95 evaluable patients was rated asexcellent or good in 94 (99%). No skin telangiectasias,significant fibrosis or persistent breast pain were noted.The authors concluded that the use of intensity modu-lation using their static multi-leaf collimator techniquefor tangential whole breast radiotherapy was an efficientmethod for achieving a uniform and standardized dosethroughout the whole breast.

7.5.2 Loco-Regional Breast|Chest Wall IMRT

In the work published on IMRT technique for treatmentof breast|chest wall and regional nodes, there is a di-vergence in methods used to approach the challenge ofbalancing target coverage and normal tissue avoidance.One direction has been to use multiple fields shapedto conform to the target, while the other continues touse deep tangential fields, but with IMRT planning andrespiratory gating.

Allmulti-field target-conformal approaches thathavebeen described report improved coverage of the targetand a reduction in the volume of normal tissue receiv-ing high doses [14, 43, 54, 55]. Kreuger et al. reportedon a ten-patient comparison between a multiple fieldIMRT technique and a partially wide tangential field ap-proach planned with conventional methods [33,43]. Allpatients chosen for study had undergone a left-sidedmodified radical mastectomy for stage II or III disease.The chest wall, defined by anatomic boundaries, supra-clavicular and internal mammary target volumes andrelevant normal tissue structures were contoured. Ageneral nine-field arrangement of equally spaced fieldsaround the patient was used. Each beam aperture wasopened to include the target volume plus 1–2 cm and anin-house inverse planning system used to determine theintensity of each beamlet. In comparison to the partiallywide tangential field approach, considered the optimalconventional technique toavoidcardiacdose, theirnine-field approach improved chest wall coverage, achievedcomparable low cardiac doses, improved internal mam-mary node coverage and reduced the left lung meandose and normal tissue complication probability. Thistechnique was successful over a range of body habitus.Despite the apparent superiority of this approach, theauthors cautioned that to achieve these results, thereis an associated penalty of increased volume of heart,lung and contralateral breast receiving low doses (i. e.,increased integral dose) and suggested that, before clin-ical implementation, a reduction in these volumes isnecessary. Lomax et al. completed a similar study oftechniques comparing a conventional photon|electrontechnique to a nine-field IMRT approach but also com-

pared a proton technique [55]. They reported similarimprovement in target coverage and normal tissueavoidance with the IMRT technique that was surpassedby the proton plan with respect to non-target integraldose andpotential riskof carcinogenesis. Cho et al. com-pared IMRT and non-IMRT techniques in the treatmentof the left breast and internal mammary nodes in twelvepatients and demonstrated superior breast and inter-nal mammary chain target coverage [54]. TangentialIMRTfieldswereused, thus removing the concernsof in-creased integral dose. Whether this technique achievesthe same results over a range of body habitus wasnot addressed. In a similar study, an inversely planned12-beam IMRT technique proved superior in target cov-erage and high dose reduction to normal structuresbut re-iterated the associated increase in integral dose[56]. These techniques have yet to be clinically tested.It remains unknown whether the high dose reductionto the underlying heart and lung is clinically relevantand whether the increased volume of lung, heart andcontralateral breast will become clinically relevant.

The alternate approach to this treatment problem hasbeen the focus of study at the William Beaumont Hos-pital. Their approach is based on the continued use ofdeep tangentialfieldswith IMRT-enhanceddosimetry inconjunction with active breathing control (ABC) using amoderately deep inspiration breath hold (mDIBH) tech-nique [17,18]. The application of tangential fields avoidsthe concerns of increased integral dose and the associ-ated concerns of late toxicity. The mDIBH techniqueimproves the geometry of the normal tissue and criticalorgan anatomical relationship, thus allowing improvedbreast|chestwall and internal mammary node cover-age while reducing high dose regions to the underlyingheart.

7.6 Future Directions|Conclusion

The use of IMRT in the treatment of breast cancer is in-creasing across the U.S. as a result of the improvementsprovided in dose homogeneity and normal tissue avoid-ance. The application of IMRT offers reduced soft tissuetoxicity in isolated breast treatment and the potential forimproved local-regional control without an increase inlung and heart toxicity in those requiring loco-regionaltreatment. When standard tangential fields are used todefine the target volume, the focus of IMRT is primarilyto optimize dose homogeneity. Although long term out-come studies are needed to make definitive statements,many have already accepted this treatment approachas a preferred method of treatment delivery. However,when dose conformality becomes a primary focus,manyuncertainties arise that require additional study priorto widespread adoption. By generating highly confor-mal fields with severe dose gradients, the accuracy of

380 III. Clinical

treatment delivery becomes increasingly dependant onset up error and breathing motion. This is not an is-sue when standard tangents are used for isolated breasttreatment as the generous field design allows the targetto remain in the field despite inter or intra-fraction mo-tion. However, this is a critical issue when dose shapingwith the goal of maximizing target coverage and normaltissue avoidance. Future investigation will need to ad-dress these challenges before IMRT can be consideredforwidespreadadoption.Additionally, long termfollow-up is needed to determine whether the improvements indose homogeneity and conformality will translate intoimprovements in disease control and|or a reduction intoxicity.

References

1. Fischer B, Anderson S, Bryant J et al. (2002) Twenty-yearfollow-up of a randomized trial comparing total mastec-tomy, lumpectomy, and lumpectomy plus irradiation for thetreatment of invasive breast cancer. N Engl J Med 347:1233–1241

2. Veronesi U, Cascinelli N, Mariani L et al. (2002) Twenty-yearfollow-up of randomized study comparing breast-conservingsurgery with radical (Halstead) mastectomy for early breastcancer. N Engl J Med 347:1227–1232

3. Overgaard M, Hansen PS, Overgaard J et al. (1997) The DanishBreast Cancer Cooperative Group 82b Trial. New Eng J Med337:949–955

4. Ragaz J, Jackson SM, Le N et al. (1997) Adjuvant radiotherapyand chemotherapy in node-positive premenopausal womenwith breast cancer. New Eng J Med 337:956–962

5. Wazer DE, Dipetrillo T, Schmidt-Ullrich R et al.(1992) Fac-tors influencing cosmetic outcome and complication risk afterconservative surgery and radiotherapy for early stage breastcarcinoma. J Clin Oncol 10:356–363

6. Potters L, Steinberg M, Wallner P et al. (2003) How one definesintensity-modulated radiation therapy. Int J Radiat Oncol BiolPhys 56:609–610

7. Glatstein E (2003) The return of the snake oil salesmen. Int JRadiat Oncol Biol Phys 55:561–562

8. Glatstein E (2002) Intensity-modulated radiation therapy: theinverse, the converse, and the perverse. Semin Radiat Oncol12:272–281

9. Strom EA (2002) Breast IMRT: new tools leading to new vision.Int J Radiat Oncol Biol Phys 54:1297–1298

10. Fischer B, Bower M, Margolese R et al. (1985) Five year resultsof a randomized clinical trial comparing total mastectomyand segmental mastectomy with or without radiation in thetreatment of breast cancer. N Engl J Med 312:665–673

11. Carruthers LJ, Redpath AT, Kunkler IH (1999) The use ofcompensators to optimize the three dimensional dose distri-bution in radiotherapy of the intact breast. Radiother Oncol50:291–300

12. Hong L, Hunt M, Chui C et al. (1999) Intensity-modulatedtangential beam irradiation of the intact breast. Int J RadiatOncol Biol Phys 44:1155–1164

13. Li JG, Williams SS, Goffinet DR et al. (2000) Breast-conservingradiation therapy using combined electron and intensity-modulated radiotherapy technique. Radiother Oncol 56:65–71

14. Thilmann C, Zabel A, Nill S et al. (2002) Intensity-modulatedradiotherapy of the female breast. Med Dosim 27:79–90

15. KorevaarEW,HutzengaH,Lof J et al. (2002) Investigationof theadded value of high-evergy electroms in intensity-modulatedradiotherapy: four clinical cases. Int J Radiat Oncol Biol Phys52:236–253

16. Fogliatta A, Bolsi A, Cozzi L (2002) Critical appraisal oftreatment techniques based on conventional photon beams,intensity modulated photon beams and proton beams fortherapy of intact breast. Radiother Oncol 62:137–145

17. Remouchamps VM, Vicini FA, Sharpe MB et al. (2003) Sig-nificant reductions in heart and lung doses using deepinspiration breath hold with active breathing control andintensity-modulated radiation therapy for patients treatedwith locoregional breast irradiation. Int J Radiat Oncol BiolPhys 55:392–406

18. Remouchamps VM, Letts N, Vicini FA et al. (2003) Initial clin-ical experience with moderate deep-inspiration breath holdusing an active breathing control device in the treatment ofpatients with left-sided breast cancer using external beam ra-diation therapy. Int J Radiat Oncol Biol Phys 56:704–715

19. Gyenes G, Rutqvist LE, Liedberg A et al. (1998) Long-termcardiac morbidity and mortality in a randomized trial of pre-and postoperative radiation therapy versus surgery alone inprimary breast cancer. Radiother Oncol 48:185–190

20. Cuzick J, Stewart H, Rutqvist L et al. (1994) Cause-specific mor-tality in long-term survivors of breast cancer who participatedin trials of radiotherapy. J Clin Oncol 12:447–453

21. Whelan TJ, Julian J, Wright J et al. (2000) Does locoregionalradiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18:1220–1229

22. Pierce LJ, Butler JB, Martel MK et al. (2002) Postmastectomyradiotherapy of the chest wall: dosimetric comparison of com-mon techniques. Int J Radiat Oncol Biol Phys 52:1220–1230

23. Arthur DW, Arnfield MR, Warwicke LA et al. (2000) Internalmammary node coverage: an investigation of presently ac-cepted techniques. Int J Radiat Oncol Biol Phys 48:139–146

24. Marks LB, Hebert ME, Bentel G et al. (1994) To treat or notto treat the internal mammary nodes: A possible compromise.Int J Radiat Oncol Biol Phys 29:903–909

25. Romestaing P, Lehinge Y, Carrie C et al. (1997) Role of a 10-Gy boost in the conservative treatment of early breast cancer:results of a randomized clinical trial in Lyon, France. J ClinOncol 15:963–968

26. Bartelink H, Horiot JC, Poortmans P et al. (2001) Recurrencerates after treatment of breast cancer with standard radio-therapy with or without additional radiation. N Engl J Med345:1378–1387

27. Whelan T, MacKenzie R, Julian J et al. (2002) Randomized trialof breast irradiation schedules after lumpectomy for womenwith lymph node-negative breast cancer. J Natl Cancer Inst94:1143–1150

28. Arthur DW (2003) Accelerated partial breast irradiation: achange in treatment paradigm for early stage breast cancer(guest editorial). J Surg Oncol 84:185–191

29. Singla R, King S, Albuquerque K, Creech S, Dogan N (2003)Simultaneous integrated IMRT boost in the treatment of earlystage left-sided breast carcinoma, presented at 2003 RSNAmeeting in Chicago, IL. Abstract 1512, p 694, RSNA meetingproceedings (2003)

30. Sasieni PD, Adams J, Cuzick J (2002) Avoidance of prematuredeath: a new definition for the proportion cured. J CancerEpidemiol Prev 7:165–171

31. Gyenes G, Gagliardi G, Lax I et al. (1997) Evaluation of irradi-atedheart volumes in stage Ibreast cancerpatients treatedwith

381Douglas W. Arthur, Monica M. Morris, Frank A. Vicini, Nesrin Dogan Chapter 7 Breast IMRT

postoperative adjuvant radiotherapy. J Clin Oncol 15:1348–1353

32. Das IJ, Cheng EC, Freedman G et al. (1998) Lung and heart dosevolume analysis with CT simulator in radiation treatment ofbreast cancer. Int J Radiat Oncol Biol Phys 42:11–19

33. Marks LB, Munley MT, Spencer DP et al. (1997) Quantifica-tion of radiation-induced regional lung injury with perfusionimaging. Int J Radiat Oncol Biol Phys 38(2):399–409

34. Lind P, Marks LB, Hardenbergh PH et al. (2002) Technicalfactors associated with radiation pneumonitis after local plusor minus regional radiation therapy for breast cancer. Int JRadiat Oncol Biol Phys 52(1):137–143

35. Hardenbergh PH, Munley MT, Bentel GC et al. (2001) Cardiacperfusion changes in patients treated for breast cancer withradiation therapy and doxorubicin: preliminary results. Int JRadiat Oncol Biol Phys 49(4):1023–1028

36. Lind PA,Pagnanelli R,Marks LBet al. (2003) Myocardial perfu-sion changes in patients irradiated for left-sided breast cancerand correlation with coronary artery distribution. Int J RadiatOncol Biol Phys 55(4):914–920

37. Gagliardi G, Lax I, Soderstrom S et al. (1998) Prediction ofexcess risk of long-term cardiac mortality after radiotherapyof stage I breast cancer. Radiother Oncol 46(1):63–71

38. Landau D, Adams EJ, Webb S et al. (2001) Cardiac avoid-ance in breast radiotherapy: a comparison of simple shieldingtechniques with intensity-modulated radiotherapy. RadiotherOncol 60:247–255

39. Vicini FA, Sharpe M, Kestin L et al. (2002) Optimizing breastcancer treatment efficacy with intensity-modulated radiother-apy. Int J Radiat Oncol Biol Phys 54:1336–1344

40. Hall EJ, Wu CS (2003) Radiation-induced second cancers: theimpact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys56:83–88

41. Obedian E, Fischer DB, Haffty BG (2000) Second malignanciesafter treatment of early-stage breast cancer: lumpectomy andradiation therapy versus mastectomy. J Clin Oncol 18:2406–2412

42. Taghian A, de Vathaire F, Terrier P et al. (1991) Long-term riskof sarcoma following radiation treatment for breast cancer. IntJ Radiat Oncol Biol Phys 21:361–367

43. Kreuger EA, Fraass BA, McShan DL et al. (2003) Potentialgains for irradiation of chest wall and regional nodes withintensity modulated radiotherapy. Int J Radiat Oncol Biol Phys56:1023–1037

44. Johansson J, Isacsson U, Lindman H et al. (2002) Node-positiveleft-sided breast cancer patients after breast-conserving

surgery: potential outcomes of radiotherapy modalities andtechniques. Radiother Oncol 65:89–98

45. George R, Keall PJ, Kini VR et al. (2003) Quantifying the effectof intrafraction motion during breast IMRT planning and dosedelivery. Med Phys 30:552–562

46. Hector CL, Evans PM, Webb S (2001) The dosimetric conse-quences of inter-fractional patient movement on three classesof intensity-modulated delivery techniques in breast radio-therapy. Radiother Oncol 59:281–291

47. Evans PM, Donovan EM, Partridge M et al. (2000) The deliv-ery of intensity modulated radiotherapy to the breast usingmultiple static fields. Radiother Oncol 57:79–89

48. Zackrisson B, Arevarn M, Karlsson M (2000) OptimizedMLC-beam arrangements for tangential breast irradiation.Radiother Oncol 54:209–212

49. Lo YC, Yasuda G, Fitzgerald TJ et al. (2000) Intensity modu-lation for breast treatment using static multi-leaf collimators.Int J Radiat Oncol Biol Phys 46:187–194

50. Chang SX, Deschesne KM, Cullip TJ et al. (1999) A compar-ison of different intensity modulation treatment techniquesfor tangential breast irradiation. Int J Radiat Oncol Biol Phys45:1305–1314

51. Chui CS, Hong L, Hunt M et al. (2002) A simplified intensitymodulated radiation therapy technique for the breast. MedPhys 29:522–529

52. van Asselen B, Raaijmakers CP, Hofman P et al.(2001) An im-proved breast irradiation technique using three-dimensionalgeometrical information and intensity modulation. RadiotherOncol 58:341–347

53. Kestin LL, Sharpe MB, Frazier RC et al. (2000) Intensity mod-ulation to improve dose uniformity with tangential breastradiotherapy: initial clinical experience. Int J Radiat OncolBiol Phys 48:1559–1568

54. Cho BC, Hurkmans CW, Damen EM et al. (2002) Intensitymodulated versus non-intensity modulated radiotherapy inthe treatment of the left breast and upper internal mammarylymph node chain: a comparative planning study. RadiotherOncol 62:127–136

55. Lomax AJ, Cella L, Weber D et al. (2003) Potential role ofintensity-modulated photons and protons in the treatment ofthe breast and regional nodes. Int J Radiat Oncol Biol Phys55:785–792

56. Thilmann C, Sroka-Perez G, Krempien R et al. (2004) Inverselyplanned intensity modulated radiotherapy of the breast in-cluding the internal mammary chain: a plan comparison study.Technol Cancer Res Treat 3:69–75