Breast IMRT

Breast IMRT

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

7

Contents

7.1 The Clinical Problem . . . 371

7.1.1 Isolated Breast Treatment . . . 371

7.1.2 Loco-Regional Breast|Chest Wall Treatment . . 372

7.1.3 Simultaneous Integrated Boost (SIB) . . . 373

7.2 Unique Anatomical Challenges . . . 373

7.2.1 Lung and Heart Avoidance . . . 373

7.2.2 Inter- and Intra-Fraction Motion . . . 374

7.3 Breast Volume Delineation . . . 375

7.4 Planning and Dose Prescriptions . . . 375

7.4.1 Isolated Breast . . . 375

7.4.2 Loco-Regional Breast|Chest Wall IMRT . . . . 376

7.5 Clinical Experience . . . 377

7.5.1 Isolated Breast IMRT . . . 377

7.5.2 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 management of breast cancer patients throughout the spectrum of the disease: from adjuvant treatment of early and locally advanced stage to palliative treatment of metastasis. In the adjuvant setting there are two distinct clinical situ- ations; (1) treatment of the breast only following breast conserving surgery for early stage disease and (2) treat- ment to the breast | chest wall and regional nodes for locally advanced disease. The use of radiotherapy in these clinical settings has been shown to improve local, local-regional control and overall survival [1–4]. When radiotherapy was first introduced into these clinical set- tings, broad field designs were used. These original broad fields were simplistic in design, and limited by the planning and treatment delivery systems available.

However, because of their simplicity, success in reducing disease recurrence, and ease of implementation, these treatment techniques quickly became widely adopted. In fact, the majority of treatment centers today continue the

same general disease management principles and treat- ment approaches originally designed and practiced in the 1970s and 1980s. Although upgraded field matching techniques and CT based treatment planning have been incorporated in many centers, minimal modifications have been made until recently with the emergence of im- age based treatment planning and advanced, intensity modulated radiotherapy delivery techniques. Intensity Modulated Radiotherapy (IMRT) in the treatment of breast cancer offers improved dose conformality and homogeneity. Only through appropriate investigation will we be able to determine whether this improvement in dose delivery actually translates into a clinical ben- efit and, therefore, justify widespread adoption of this treatment technology.

7.1.1 Isolated Breast Treatment

Treatment of the whole breast following lumpectomy to

achieve in-breast disease control has been documented

to be successful in both local control and cosmetic out-

come [1, 2, 5]. The use of parallel opposed tangential

fields, with varying levels of mechanical compensa-

tion, has become the standard whole-breast treatment

approach due to its straight-forward simplicity, and fa-

miliarity of use from large randomized trials. The need

for improvements in these simple but effective treatment

approaches has been challenged and, therefore, it is ap-

propriate to evaluate what improvements can be realized

with IMRT [6–8]. As local control rates are primarily de-

pendent on appropriate surgical resection followed by

modest doses of adjuvant radiotherapy, improved dose

coverage of the breast target or dose escalation for tu-

mor control may not be necessary. It has been suggested

that the application of IMRT forces physicians to fo-

cus attention on target delineation and target coverage

therefore possibly yielding an improvement in disease

control [9]. However, this advantage would not be a re-

sult of treatment delivered with IMRT technology but

rather a result of the target-focused planning process

which can also be achieved through appropriate applica-

tion of conventional treatment techniques. The potential

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

Although it is recognized that, in many women, ap- propriate use of mechanical wedges produces acceptable homogeneity, management of moist desquamation in the inframammary fold and low axilla is often nec- essary and late breast fibrosis (inframammary fold fibrosis), breast edema and costochondral discomfort are frequently encountered. Possibly due to the ease of standard tangential treatment, the successful local con- trol rates and the significant improvement of life quality over mastectomy, these toxicities have been accepted as a part of the standard of care. Initially, it was com- mon to follow the treatment guidelines used in NSABP B-06, where uncompensated tangential fields (i. e., no wedge filters used) were prescribed to midplane at a point two-thirds the distance from the skin to the base of the tangent at central axis [10]. As a result, the ante- rior aspect of the treated breast received a daily dose and total dose that exceeded the prescription dose, masking the fact that doses higher than 50 Gy to the surgical bed were often delivered. The degree of this inhomo- geneity would have been variable as it is dependent on the size and shape of the breast. In the absence of dosimetric information, the effect is difficult to quan- titate. Recognizing the varying level of inhomogeneity with such an approach, wedge filters have since been universally adopted to compensate for the difference in breast width encountered. However, wedges do not compensate for three-dimensional changes and toxic- ity related to dose inhomogeneity is still encountered.

Mechanical lead compensators have been described as a method of providing customized compensation that achieves a highly homogeneous dose distribution [11].

This approach has been adopted in some centers but has never achieved widespread use as planning, compen- sator construction and treatment delivery times have been viewed as excessive, despite dosimetric benefits.

The emergence of IMRT and multi-leaf collimation has provided an electronic method of 3D compensation that addresses these difficulties by providing an automated method of delivering a homogeneous dose. For this and other reasons, IMRT has the potential to become the preferred method of radiation delivery for breast cancer.

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

the dose reductions are marginal and of questionable clinical benefit when standard tangential field arrange- ments are used [12]. Creative multi-field arrangements have also been attempted, but the added complexity and associated increase in integral dose without the obvious potential for clinical benefit has prevented acceptance into clinical use [13–15]. The proper design of standard breast-only tangential fields limits the dose delivered to the heart and ipsilateral lung to an acceptable level in the majority of women. Although patients are encoun- tered that present with a unique chest wall shape leading to an excessive amount of lung and | or heart in the field, these rare cases can usually be managed with minimal changes in tangential beam entry angle or the addition of a small heart block that reduces dose to these criti- cal structures. Alternative methods of reducing the dose to neighboring lung and heart have been studied, but not yet widely accepted and include field arrangements and controlled breath hold techniques [16–18]. Review of the late heart and lung clinical toxicity data following treatment with standard tangential fields supports the idea that further reduction of dose to the heart and lung beyond that achieved with standard tangential field is not necessary [19–21]. Therefore, the benefits of IMRT in isolated breast treatment should be focused on deliv- ering a homogeneous dose distribution throughout the breast in a population of patients with varying breast size and shape with the promise of reducing acute and late 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 in this clinical setting of locally advanced disease that there is a real potential role for IMRT due to the undeniable need 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, and

possibly the axilla presents a complicated target volume

that wraps around the immediately adjacent lung, heart,

mediastinum and brachial plexus. Many conventional

techniques have been devised and investigated for local-

regional coverage in both the settings of intact breast and

post-mastectomy treatment [22, 23]. Although many of

these techniques offer improved dosimetric coverage of

this complex target volume and a reduction in normal

tissue exposure, the partially wide tangent technique

offers the best balance between target coverage and

reduction in heart and lung dose [24]. However, it is

recognized that there is no universally successful tech-

nique in a population presenting with widely varying

thoracic structure and breast dimensions. One of the

more obvious concerns with the inclusion of the inter-

nal mammary nodes is the resultant increase in dose

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

7.1.3 Simultaneous Integrated Boost (SIB)

Several studies have indicated that delivering a boost dose to the tumor bed plus margin, typically with elec- trons, following conventional whole breast radiotherapy results in improved in-breast control rates [25, 26]. De- spite the documented local control benefit, the design of these boost fields in many practices remains a clinical process based on mammograms, clinical exam and site of surgery. CT-based planning has opened the eyes of radiation oncologists, revealing the potential for boost field design error if image guidance is not incorporated into the boost field planning process. With the advanced planning process of IMRT, there emerges the potential for incorporating the boost dose into the whole breast dose delivery, therefore simultaneously delivering the boost dose – simultaneous integrated boost, SIB. This would facilitate shortening the treatment course deliv- ery time by one to two weeks while potentially improving the conformance of the boost dose to the boost target.

Minimal investigational work has been completed in this area, possibly related to the high rates of local con- trol seen with present boosting techniques and because shortening the treatment course to five to five-and-a- half weeks is not remarkable compared to achievements with newer techniques accelerating the overall treat- ment course further and completing in three- and-a-half weeks or even in five days [27, 28]. It is uncertain at this time whether SIB can be incorporated into stan- dard practice and further investigation is needed to address several questions. These questions include the design of reliable field arrangements that would allow SIB dose delivery and avoid increase dose delivery to surrounding normal tissue and critical organs. SIB is based on the ability to deliver an incremental daily dose increase to the boost target while continuing delivery of standard doses to the remainder of the breast. The amount of dose increase that will result in equivalent tu- mor control and breast tissue toxicity rates experienced with present techniques has not yet been determined.

Lastly, additional daily treatment time will be required to deliver this treatment approach. Whether the benefit of applying IMRT technology in this situation justifies the additional time needed to plan and deliver treat- ment with a SIB is unknown and requires additional investigation.

An example of early investigation into the use of SIB with whole breast irradiation is described by Singla et al.

[29]. They investigated the feasibility of SIB-IMRT for treatment of ten early stage left-sided invasive breast car-

cinoma patients. They compared target volume coverage and normal tissue dose using SIB-IMRT using six-field non-coplanar fields to traditional tangential fields op- timized with wedges or compensating filters with an en-face electron lumpectomy bed boost. Their results showed that there was no difference seen in the cover- age of left breast and lumpectomy bed using SIB-IMRT vs conventional 3D CRT. However, the plans generated with SIB-IMRT were significantly more conformal than all other plans. Their study also showed that SIB-IMRT significantly reduced the maximum dose to the left lung by ∼22%. However, this benefit came at the expense of increased left breast dose outside of the lumpectomy bed, a direct result of the simultaneous boost. They concluded that although the use of a simultaneous in- tegrated boost to the lumpectomy bed seems feasible, the clinical consequences of the increased ipsilateral breast dose remains unknown and therefore should be investigated further.

7.2 Unique Anatomical Challenges

7.2.1 Lung and Heart Avoidance

As modern treatment techniques allow us the luxury of working 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 important consideration. In breast cancer, early techniques, such as the hockey stick approach, were effective, though the improvement in survival was offset by excess treatment- related cardiac morbidity. More modern techniques (tangents) continue to demonstrate an improved disease control with acceptable normal tissue toxicity [19–21].

The goal of IMRT is to decrease further treatment toxi- city while concurrently maintaining early stage disease control and | or increasing locally advanced disease con- trol.

Current standard treatment techniques typically en- tail full-dose treatment to at least 10–15% ipsilateral lung volume and 3–6% of the heart volume for breast- only tangents [31, 32]. Greater treated volumes on the order of 15–25% for lung and 10–25% for heart can be expected for treatment involving the regional nodes (internal mammary chain, supraclavicular fossa, axilla).

Marks et al. have attempted to quantify lung injury after

radiotherapy using SPECT imaging [33]. They demon-

strated that for most patients there was a statistically

significant, dose-dependent reduction in regional blood

flow at all time points following pulmonary irradiation,

developing within three to six months post therapy at

doses above 5–10 Gy. Such treatment has a reported

clinical pneumonitis rate of between 1 and 4% [34].

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

As mentioned above, breast-only tangent radiother- apy is associated with a quite low but real risk of pneumonitis and cardiac disease. A number of studies of isolated breast IMRT have consistently demonstrated improved target volume dose homogeneity, a modest improvement in normal tissue sparing, with an asso- ciated increase in the mean doses to the contralateral breast and lung [14, 38, 39]. Isolated breast IMRT has been successfully implemented in the clinic with ex- cellent cosmetic and acute complication results [39];

however, it will take lengthy follow-up of many more patients thus treated to demonstrate any incremental improvement in an already-low toxicity profile.

As opposed to simple tangents, the use of IMRT in the setting of locally advanced disease, with treatment of the regional nodes, may prove to be more compelling and 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 of IMRT for local-regional breast cancer treatment likely relates to concerns about set-up accuracy, organ motion and increased integral dose. Increased integral dose, as is consistently demonstrated in IMRT planning studies, may be associated with a near-doubling of the induced malignancy rate [40]. While the risk of second malig- nancy with radiotherapy is so low as to be statistically insignificant 15 years post-therapy, it does remain a real consideration, particularly amongst our younger patients [41, 42].

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

Table 1.Conservative normal tissue constraints presently applied at VCU

Normal tissue Dose limit

Ipsilateral lung < 5 Gy to < 30% of lung

< 20 Gy to < 10% of lung 0 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 volume 40 Gy to < 3% of total heart volume

dose to contralateral lung and breast increased. Johans- son et al. present similar findings in their planning study of standard photons, IMRT and proton therapy for node positive left-sided breast cancer treatment [44]. In this study, mean NTCP for heart decreased from 7% with standard tangents to 2% and to 0.5% with IMRT and protons, respectively. NTCP for the left lung remained 28% for both tangents and IMRT and decreased to 0.6%

for protons.

Most of the data used to set lung and heart dose constraints is generated from patients treated for lung cancer and other malignancies where the disease pro- cess frequently outpaces the development of late normal tissue toxicity. Therefore, when treating young patients, setting definitive normal tissue constraints is difficult as the late effects of treating large volumes of normal tissue to low doses are not known. When constraints are set, they tend to be conservative, see Table 1, which often becomes restrictive and may limit or potentially inhibit the ability of the IMRT planning process to achieve the desired dose conformality. Until additional data is available, a reasonable approach to setting nor- mal tissue constraints and determining cost functions is to use normal tissue dose tolerances derived from data observed in other organ sites or to use clinically acceptable dose | volume data generated from standard plans | techniques that have resulted in acceptable rates of 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- and

intra-fraction motion is not a significant factor. It is as-

sumed that any movement of the true target, which lies

within the confines of the breast tissue, moves within

the fields as defined by the previously discussed con-

ventional methods. However, that assumption cannot

be extrapolated to local-regional treatment. The inter-

nal mammary lymph nodes are located in immediate

proximity to the lung and heart and the dose is tightly

conformed to the target structure in order to minimize

normal tissue dose and avoid toxicity. Because of the

sharp dose fall-off at the field edge and the tight confor- mality of dose, intra-fraction movement, as a result of breathing, may be a factor confounding accurate dose delivery. Studies exploring this potential pitfall indicate that normal breathing motion results in approximately 5 mm of position change and that this movement has lit- tle effect on dose homogeneity within the clinical target volume (CTV) [45, 46]. Fraction to fraction differences can be seen; however, due to the interplay between respi- ratory motion and multi-leaf collimator motion during treatment delivery. Over a full course of treatment, how- ever, there are no statistical differences between the planned and expected dose distributions. An effect of breathing motion that may require attention when treat- ing a local-regional target is the resultant degradation of the planning target volume (PTV) dose uniformity that requires an increase in CTV to PTV expansion [45]. In addition, lung and heart doses also increase.

Breath-hold, respiratory gating and 4D techniques can limit motion effect and remove the need for additional CTV-PTV expansion.

7.3 Breast Volume Delineation

In keeping with the IMRT planning principles used in other treatment sites, the planning of breast-only IMRT begins with the accurate delineation of target and crit- ical normal tissue volumes. In breast-only treatment, conformal coverage of the breast immediately becomes problematic because of the inability to reliably define the extent of breast tissue and, therefore the target, to be treated. Many publications discussing IMRT for breast cancer simply state that the breast volume was entered for planning, and the volumes depicted in publication vary widely. However, in reality breast tissue extent can- not be reliably defined on CT scan and therefore this process translates into the entry of a breast target con- tour that is manually delineated relying on knowledge of breast anatomy, external skin contour and often ex- ternal markers that are placed prior to CT to delineate breast tissue extent based on palpation. This approach results in the uncomfortable situation of planning the delivery of a highly conformal treatment to a target that is subjectively delineated. One solution has been to rec- ognize that treatment using standard tangential fields has historically resulted in excellent local control, and so to assume that the clinical methods of defining these fields reliably covers the target and, therefore, can also be used to define the target for IMRT. As a result of this thinking, many of the various published IMRT tech- niques define the breast tissue by designating all tissue within standard tangential fields, excluding lung, as the breast target. Others have developed dose optimization approaches that simply assure dose uniformity to all tissue within the tangential fields.

7.4 Planning and Dose Prescriptions

7.4.1 Isolated Breast

Although it is recognized that there are physicians who prefer to have the breast volume contour entered free- hand on each CT cut, at the Virginia Commonwealth University we have found that the contouring of the target volume is efficient and consistent when the con- tour is automated and guided by standard tangential field borders. Using tangential field borders, designed with clinical and CT guidance, the planning system can be programmed to auto-contour the target by in- cluding all tissue within the tangential field borders excluding lung. Although the chest wall is included within the breast reference volume, this has little impact on the final dose distribution due to the effect of the lung | chest wall interface on the final dose distribution.

We additionally retract the contour 5 mm from the skin surface to account for dose build up. The IMRT plans are generated to be delivered with the step-and-shoot technique that employs the segmented multi leaf colli- mator (sMLC). All treatments are planned using 6-MV photon beams. The inverse planning optimization is per- formed using the Pinnacle [3] planning system (Philips laboratories, Milpitas, CA). A pencil beam calculation al- gorithm is used during optimization and the final dose is calculated, with heterogeneity corrections, using a superposition | convolution algorithm after the leaf se- quencing is determined. The dosimetric goal for isolated breast IMRT is to achieve 95% target volume coverage with 100% of the prescription dose. Lung and heart volumes are not considered when optimizing the dose distribution as it is assumed that the volumes included

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

Fig. 2. Breast volume dose volume histogram

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

Treating with standard tangential fields, where wedges are the only form of tissue compensation used, often results in significant areas inhomogeneity that are typically 10–15% greater than the prescribed dose. The degree of inhomogeneity is dependant on breast size and shape. Acute and late breast and overlying skin toxicity are typically experienced, most commonly in the infra-mammary fold. These normal tissue effects manifest as moist desquamation with subsequent risk of telangiectasia and | or degree of fibrosis. With IMRT planning and dose delivery these areas of increased dose can be reduced with a correlative improvement in toxi- city. Figures 1 and 2 illustrate the improvements in dose distribution that can be achieved with IMRT planning as compared with results from standard planning using wedge compensation.

7.4.2 Loco-Regional Breast | Chest Wall IMRT

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

The spatial relationship between the loco-regional target and the underlying lung and heart is challenging and presently described approaches either compromise

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

on target coverage or accept an increase in dose to normal structures. In our preliminary investigation, we have evaluated a two-field 3D-CRT, and a two-, six- and nine-field IMRT approach and compared dose distribu- tions as they relate to loco-regional target coverage and normal tissue avoidance. Initially, we set conservative normal tissue constraints, Table 1. Plans covering the breast 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)

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 compared to a two-field IMRT plan, a six-field non-coplanar beam IMRT plan, and an IMRT plan using nine equally spaced coplanar beams. The gantry angles used for the six-beam arrangement were designed such that the sparing of or- gans at risk was maximized and fields were positioned at angles of 305, 125, 325, 145, 105, and 345

. Plans were optimized for breast target coverage and normal tissue avoidance. Single CT cut dose distribution comparison of these four-field arrangements is depicted in Fig. 3.

The spatial relationship between the loco-regional tar- get and critical organ structures changes from superior to inferior and therefore a three-dimensional dose com-

Goal dose to

% lung vol

Actual lung volume receiving dose Control

3DCRT

2 Fld 6 Fld 9 Fld

IMRT 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 Control

3DCRT

2 Fld 6 Fld 9 Fld

IMRT 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 volume

covered by the % of the prescription dose

Treatment technique Control

3DCRT (%)

2 Fld 6 Fld 9 Fld

IMRT 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 differences between treatment approaches. The Dose Volume His- tograms comparing the four techniques for both lung and heart are seen in Figures 4 and 5. Note that all treat within a range that is acceptable by known criteria. The dose received by percent of organ at risk for the evalu- ated techniques is displayed in tabular format in Tables 2 and 3 and the ability of each technique to cover the IMN target volume detailed in Table 4. This preliminary study suggests that the best balance between target cov- erage, as signified by internal mammary node coverage and normal tissue avoidance, appears to be achieved with a two-field IMRT approach.

7.5 Clinical Experience

7.5.1 Isolated Breast IMRT

Many institutions have investigated breast-only IMRT with the goal of improving dose homogeneity. The majority of publications are dosimetric studies, with rare clinical experiences reported. All studies report improved homogeneity of dose throughout the breast target with IMRT techniques as compared to standard wedged tangential fields. Most investigators report tech- niques using standard tangential field arrangements with differences existing in the methodology used to define the treatment target, to obtain the desired dose distribution, and to deliver the planned dose. Inverse planning and various forms of forward planning have been used to generate homogeneous treatment plans that can be delivered with mechanical compensators, with computer controlled multi-leaf collimation (MLC) utilizing multiple static fields, or with dynamic IMRT treatment delivery.

Three institutions have described IMRT techniques

that incorporate multiple static fields delivering low dose

to enhance the dose homogeneity of standard wedged

tangential fields [47–49]. Starting with the majority of

the dose delivered with fields optimized with wedges

only, Zackrisson et al. and Lo et al. fashioned additional fields which deliver a portion of the dose to the target excluding the higher dose regions [48, 49]. These addi- tional fields were created with a 3D treatment planning system through an iterative process. Similarly, Evans et al. began the treatment delivery design with wedged fields and augmented the dose delivery with a set of low-dose shaped fields based on thickness maps ob- tained with an electronic portal imaging device [47]. All three studies demonstrated a reduction of the high dose regions within the breast. Chang et al. evaluated eight different 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 dose optimization algorithm and delivered via the compen- sator and MLC techniques. They have also reported that the contralateral breast dose is maximally reduced with collimator generated techniques, i. e. MLC or virtual wedge. However, the MLC technique requires the longest treatment irradiation time.

With several publications demonstrating improved dose uniformity with IMRT, the importance of reduc- ing treatment planning and delivery time becomes an issue if the use of IMRT for breast cancer is to be prac- tical enough to be used in a busy clinic. This conversion to a practical, time efficient approach is exemplified in the publications from Memorial Sloan Kettering Can- cer Center. Hong et al., initially presented a dosimetric study of five patients with right and five patients with left breast involvement [12]. They presented an inverse planning IMRT technique utilizing set target and crit- ical organ optimization criteria and compared this to standard wedged tangential fields. They reported an improvement in dose homogeneity, with an 8% dose reduction in the superior and inferior aspects of the breast target and 4% in the medial and lateral, as well as a reduction in the dose delivered to the coronary artery region, ipsilateral lung and contra-lateral breast.

Although improvements in normal tissue doses and tar- get dose homogeneity were evident, the concern was raised that these improvements may not be on a large enough scale to justify the huge increase in planning ef- fort required for such inverse methods. In response to this report, a simplified and efficient IMRT technique for the breast, referred to as simplified IMRT (sIMRT), was developed [51]. The standard tangential beam ar- rangement was used and contours, except the automated external contour, were eliminated. The PTV was defined as all tissue within the tangential fields, less 5 mm beam penumbra and 5 mm from skin. For each field, a pen- cil beam grid was created and the optimal intensity of each pencil beam determined as proportional to the in- verse of the midpoint dose from an open beam. The intensity distribution was then converted to a deliv- erable plan utilizing multi-leaf collimation. In fifteen

patients the sIMRT planning technique was compared to the standard wedged pair tangential field technique and volume based IMRT technique (vIMRT). They re- ported that the target dose homogeneity and normal tissue dose limitation was equivalent between sIMRT and vIMRT planning. However, the planning time for sIMRT was significantly less than that for vIMRT and equivalent to the planning time for standard wedged fields, thus converting the planning technique to one which can be adopted in clinics treating high volumes of patients.

Similarly, two additional methods have been de- scribed, both delivering the majority of the intended dose with open fields and supplementing with shaped low dose fields to optimize dose homogeneity through- out the field. The technique first described by van Asselen et al., delivers approximately 88% of the dose with open fields [52]. The remaining dose is given with multiple shaped fields, or segments, that are obtained from an equivalent path length map of the irradiated volume. Kestin et al. has described a similar technique, developed at the William Beaumont Hospital, where multi-leaf segments are designed based upon isodose surfaces that result from an open set of tangent fields, with each segment weight-optimized using a comput- erized algorithm [53]. Limitations are placed on the volume of tissue that can exceed the prescription and a set of rules is then used to derive a sequence of field apertures, with the weights of these apertures the free parameters in the optimization. This approach is referred to as “limited parameter set” optimization, be- cause the number of free parameters is small compared to pixel-based, or fluence map optimizations. Others have referred to this as aperture-based inverse planning, or segmental IMRT (sIMRT). This approach (an opti- mized combination of open fields and customized field apertures) allows one to compensate precisely for the changing breast contour. With treatment planning and treatment delivery times reported as less than 60 min and 10 min, respectively, we now have the tools to achieve superior dose homogeneity in a time efficient manner [39].

Limited data is available regarding any clinical expe- rience with IMRT-based treatment of breast cancer. The largest clinical experience with whole-breast IMRT was recently published by the William Beaumont Hospital group [39]. Two hundred and eighty one patients, with early stage breast cancer and electing breast conserv- ing therapy, received whole breast radiotherapy after lumpectomy using an sIMRT technique. The technical and practical aspects of implementing this technique on a large scale in the clinic were analyzed, as well as the acute toxicity and cosmetic outcome of the patients.

Treatment time was equivalent to conventional wedged-

tangent treatment techniques. The median volume of

breast receiving 105% and 110% of the prescribed dose

was 11% (range 0–68%) and 0% (range 0–39%), re-

spectively. No or mild acute skin toxicity was noted in 56% of patients. Forty three percent experienced moder- ate, grade II, acute skin toxicity, and only three patients (1%) had significant, grade III toxicity. Cosmetic result at year one in the 95 evaluable patients was rated as excellent 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 technique for tangential whole breast radiotherapy was an efficient method for achieving a uniform and standardized dose throughout the whole breast.

7.5.2 Loco-Regional Breast | Chest Wall IMRT

In the work published on IMRT technique for treatment of breast | chest wall and regional nodes, there is a di- vergence in methods used to approach the challenge of balancing target coverage and normal tissue avoidance.

One direction has been to use multiple fields shaped to conform to the target, while the other continues to use deep tangential fields, but with IMRT planning and respiratory gating.

All multi-field target-conformal approaches that have been described report improved coverage of the target and a reduction in the volume of normal tissue receiv- ing high doses [14, 43, 54, 55]. Kreuger et al. reported on a ten-patient comparison between a multiple field IMRT technique and a partially wide tangential field ap- proach planned with conventional methods [33, 43]. All patients chosen for study had undergone a left-sided modified radical mastectomy for stage II or III disease.

The chest wall, defined by anatomic boundaries, supra- clavicular and internal mammary target volumes and relevant normal tissue structures were contoured. A general nine-field arrangement of equally spaced fields around the patient was used. Each beam aperture was opened to include the target volume plus 1–2 cm and an in-house inverse planning system used to determine the intensity of each beamlet. In comparison to the partially wide tangential field approach, considered the optimal conventional technique to avoid cardiac dose, their nine- field approach improved chest wall coverage, achieved comparable low cardiac doses, improved internal mam- mary node coverage and reduced the left lung mean dose and normal tissue complication probability. This technique was successful over a range of body habitus.

Despite the apparent superiority of this approach, the authors cautioned that to achieve these results, there is 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 is necessary. Lomax et al. completed a similar study of techniques comparing a conventional photon | ^electron

technique to a nine-field IMRT approach but also com-

pared a proton technique [55]. They reported similar improvement in target coverage and normal tissue avoidance with the IMRT technique that was surpassed by the proton plan with respect to non-target integral dose and potential risk of carcinogenesis. Cho et al. com- pared IMRT and non-IMRT techniques in the treatment of the left breast and internal mammary nodes in twelve patients and demonstrated superior breast and inter- nal mammary chain target coverage [54]. Tangential IMRT fields were used, thus removing the concerns of in- creased integral dose. Whether this technique achieves the same results over a range of body habitus was not addressed. In a similar study, an inversely planned 12-beam IMRT technique proved superior in target cov- erage and high dose reduction to normal structures but re-iterated the associated increase in integral dose [56]. These techniques have yet to be clinically tested.

It remains unknown whether the high dose reduction to the underlying heart and lung is clinically relevant and whether the increased volume of lung, heart and contralateral breast will become clinically relevant.

The alternate approach to this treatment problem has been the focus of study at the William Beaumont Hos- pital. Their approach is based on the continued use of deep tangential fields with IMRT-enhanced dosimetry in conjunction with active breathing control (ABC) using a moderately deep inspiration breath hold (mDIBH) tech- nique [17,18]. The application of tangential fields avoids the concerns of increased integral dose and the associ- ated concerns of late toxicity. The mDIBH technique improves the geometry of the normal tissue and critical organ anatomical relationship, thus allowing improved breast | chestwall and internal mammary node cover- age while reducing high dose regions to the underlying heart.

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 improvements

provided in dose homogeneity and normal tissue avoid-

ance. The application of IMRT offers reduced soft tissue

toxicity in isolated breast treatment and the potential for

improved local-regional control without an increase in

lung and heart toxicity in those requiring loco-regional

treatment. When standard tangential fields are used to

define the target volume, the focus of IMRT is primarily

to optimize dose homogeneity. Although long term out-

come studies are needed to make definitive statements,

many have already accepted this treatment approach

as a preferred method of treatment delivery. However,

when dose conformality becomes a primary focus, many

uncertainties arise that require additional study prior

to widespread adoption. By generating highly confor-

mal fields with severe dose gradients, the accuracy of

treatment delivery becomes increasingly dependant on set up error and breathing motion. This is not an is- sue when standard tangents are used for isolated breast treatment as the generous field design allows the target to remain in the field despite inter or intra-fraction mo- tion. However, this is a critical issue when dose shaping with the goal of maximizing target coverage and normal tissue avoidance. Future investigation will need to ad- dress these challenges before IMRT can be considered for widespread adoption. Additionally, long term follow- up is needed to determine whether the improvements in dose homogeneity and conformality will translate into improvements in disease control and | or a reduction in toxicity.

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