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Clinical aspects of intensity-modulated radiotherapy in the treatment of breast cancer
Clinical Aspects of Intensity-Modulated Radiotherapy in the Treatment of Breast Cancer Editha A. Krueger, Benedick A. Fraass, and Lori J. Pierce In recent years, interest has grown throughout the radiotherapy community in investigation and clinical application of intensity-modulated radiation therapy (IMRT) for adjuvant treatment of breast cancer. IMRT removes the usual reliance on flat (or uniform-intensity) radiation fields, and instead replaces that simple paradigm with a variable-intensity pattern that is usually determined with the aid of a computerized optimization algorithm. The main goal of much IMRT and optimization work is the delivery of more conformal plans
to the patient. Thus, IMRT has the potential to improve target coverage and reduce inhomogeneities observed within the breast (and regional lymph nodes) that are obtained with standard plans. Furthermore, IMRT may be able to reduce doses delivered to the heart and lungs, and may potentially minimize further the probability of complications from radiotherapy. Copyright 2002, Elsevier Science (USA). Aft rights reserved.
I ntensity-modulated radiation therapy (IMRT) .is a general term referring to any radiation technique that utilizes variable beam intensities across an irradiated volume. In recent years, IMRT has referred to intensity modulation via segmental, mini- or nmltivane, or dynamic multileaf collimator (MLC) delivery combined with inverse planning, as evidenced by the articles in this edition o f Seminars in Radiation Oncology. However, IMRT techniques used in breast cancer patients vary widely. Investigators often use the term "IMRT" to describe a specific treatment for breast irradiation, although the goals, optimization approaches, and delivery techniques can be quite different from study to study, thereby making comparisons of IMRT studies difficult. In this review, we attempt to clarify the goals, optimization approaches, and delivery techniques used in published breast IMRT studies. IMRT for the breast alone is discussed separately from that for the breast/chest wall and regional nodes, because clear differences exist between the two subjects. We highlight the clinical and technical aspects associated with IMRT and how these relate to our knowledge of standard treatment techniques for breast cancer patients. Finally, we
discuss the clinical considerations involved with the specific use of inverse planning for IMRT plan optimization.
From the Department of Radiation Oncology, University of Michigan, Ann Arbor, MI. Address reprint requests to Lori J. Pierce, MD, Department of Radiation Oncology, University of Michigan School of Medicine, 1500 E. Medical Center Drive, UHB2C-490, Box 0010, Ann Arbor, MI 48109. E-maib [email protected]. Copyright 2002, Elsevier Science (USA). All @ t s reserved. 1053-4296/02/1203-0007535.00/0 doi:l O.1053/srao.2002.32468 950
Breast-Only Treatment Rationale The breast has been successfully treated with tangential beams for many years, resulting in excellent local control rates, low rates of pulmonary and cardiac complications, and excellent cosmesis in the majority of patients. 1,2 For these reasons, many question a role for IMRT in breast-only treatment. However, standard tangents have several limitations. First, dose homogeneity across the entire breast is difficult to achieve because of the complicated geometry of the breast. Dose inhomogeneities typically exist at the entrance and exit points, the nipple, and in the most superior and inferior portions of fields (Fig 1A and B) when the breast is treated with tangents. Use of wedges and lung inhomogeneity correction reduces the dose inhomogeneity, but a fully homogenous dose distribution across the entire field is difficult to achieve with flat (unmodulated) tangential beams. These dose inhomogeneities are further exaggerated in largebreasted women, in whom the inhomogeneities have been associated with less favorable cosmetic results. 3 The standard tangent technique invariably irradiates a section of lung and sometimes a portion of the heart to full dose for left-sided lesions (Fig 1A). Furthermore, reduction in heart and lung exposure using fiat, unmodulated
Seminars in Radiation Oncology, Vol 12, No 3 (July), 2002: pp 250-259
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/
a
-, - .
Figure 2. Supraclavicular region: SCV, supraclavicular; ICV, infraclavicular; LBP, left brachial plexus.
I M R T is used. In left-sided cancers, the heart can also potentially be spared. Thus, although the use of standard tangents has been successful, there is potential for further improvement with IMRT.
Data Multiple approaches utilizing compensators or I M R T delivery of modulated intensity beams have been applied to the t r e a t m e n t of the breast. A common method for decreasing the dose inhomogeneity in the breast that is observed with standard wedge techniques makes use of mechanical compensators. 5 The t r e a t m e n t planning process for the design of these physical compensators utilizes 3-dimensional (3D) tools during an iterative optimization process. Recently, a segmental multileaf collimator technique (sMLC) has also been used to improve dose homogeneity. 6-8 Figure 1. Typical isodose distributions for standard tangents. (A) Axial view showing hot spots in yellow; (B) sagittal view showing the inhomogeneity at the superior and inferior most regions of the breast. beams is difficult to achieve because of the concave geometry of the breast and underlying chest wall. Thus, inclusion of lung and possible heart tissue in the radiotherapy field has been a known limitation of tangential irradiation. However, with the development of IMRT, further reduction in heart and lung doses can now potentially be achieved. In fact, the benefit of IMRT has been best described for concave structures, such as the chest wall, which wraps around the lung and anterior portion of the heart. 4 It may be possible to minimize the section of lung that is irradiated to full dose by tangents when
Figure 3. Internal mammary nodes (IMN) lie deep to the chest wall (CW) along the endothoracic fascia. The heart is outlined in yellow.
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The sMLC technique combines several discrete fields of radiation in order to modulate the intensity across the treatment volume. Much like the design of physical compensators, a planner utilizes 3D treatment planning tools and calculations for optimization of the multileaf collimator (MLC) segments. Others have used equivalent path length maps and transit dosimetry information from electronic portal imaging devices (EPIDs) to determine areas of dose inhomogeneity in the breast. 9,1~ The same iterative process for the addition of segments is performed to eliminate areas of over- and underdosing. The William Beaumont group recently published data on an additional technique, whereby segments were designed from isodose surfaces calculated from an open tangent field, ~l and each segment weight was then optimized using a computer algorithm. Although this automates the treatment planning process, the optimization described did not include constraints for normal tissues, such as heart and lung, in the treatment volume. Few investigators have used inverse planning with optimization parameters (ie, cost functions that specify normal tissue constraints). Chang and colleagues from the University of North Carolina performed a study comparing different intensity modulation techniques for tangential breast irradiation. ~2 An in-house dose-gradient algorithm was used to optimize segments such that maximum homogeneity in the breast was achieved with a dose limit set for nearby critical structures. Dose measurements performed in a phantom trial confirmed that less dose was delivered to the contralateral breast with sMLC compared to the standard wedge technique. Other normal structure doses were not reported. The first comprehensive cost-function specification published for breast-only treatment was described by the group from Memorial Sloan-Kettering Cancer Center. t3 Similar to the studies previously discussed, the target volume was the breast only. Dose homogeneity within the breast was a desired result. Unlike the other studies, however, the automated algorithm used in optimizing intensity profiles included constraints to multiple normal structures, specifically, ipsilateral lung, heart, contralateral breast, and surrounding soft tissue. Modest dose reductions of these normal structures and improvement in target homogeneity were observed in 10 patients. The IMRT plans consisted of 2 beams in a tan-
gential arrangement delivered with dynamic multileaf collimators (dMLC). Other groups have expanded from a 2-field beam arrangement to allow more degrees of freedom and perhaps achieve more gains with IMRT. Li and colleagues from Stanford University were among the first to incorporate additional beams and electrons in breast IMRT planning? 4 More recently, Landau and colleagues developed three IMRT techniques: a 2- and 4-field tangent-like beam arrangement, and a 6-field arc plan. ix Similar to the Memorial Sloan-Kettering study, all IMRT plans were generated using a comprehensive cost function. The IMRT techniques were compared to standard techniques, with and without heart blocking ("Pb block"). Although the Pb block plan resulted in less heart volume receiving 60% of the prescription dose compared to the IMRT techniques (Pb block, 0.1%, vs 2- to 4-field IMRT, 2.2%, vs 6-field IMRT, 7.2%), the IMRT techniques resulted in better target coverage, with a 65% minimum target dose with the Pb block plan compared to 92%, 94%, and 92% minimum target doses with 2-, 4-, and 6-field plans, respectively. However, the 4- and 6-field IMRT techniques delivered higher mean doses to the contralateral breast and lung compared to standard techniques. Thus, in this study, although the additional beams allowed for more degrees of freedom and perhaps achieved more of the specified clinical goals, these gains were tempered by the low doses of radiation delivered to regions not typically exposed using more standard techniques. This trade-off is discussed further in later sections.
Breast/Chest Wall and Regional Treatment Rationale The rationale for using IMRT for locoregional irradiation is arguably stronger than for breastonly treatment. Comprehensive locoregional irradiation includes treatment of the breast/chest wall, supraclavicular, infraclavicular, and internal mammary nodes (IMNs) (with or without axillary irradiation). Three recent randomized trials have shown a significant advantage in disease-specific and overall survival following comprehensive locoregional postmastectomy treatment. 16-18 Based on these and other studies, a
IMRT Treatment of Breast Cancer
National Institutes of Health (NIH) consensus panel recommended locoregional postmastectomy irradiation in patients with 4 or more positive axillary lymph nodes and/or T3 and T4 lesions. However, concern exists regarding the potential for increased heart exposure with inclusion of the IMNs in the target volume. This concern is amplified by the fact that a majority of these patients at high risk for distant dissemination will likely receive doxorubicin and possibly trastuzumab, two potentially cardiotoxic agents. Therefore, the use of I M R T in comprehensive locoregional therapy is justified, if it can be shown to further improve target homogeneity compared to standard techniques, and further reduce heart and lung exposure to doses lower than those currently achieved.
Technical Considerations for IMRT The targets for locoregional t r e a t m e n t include breast/chest wall, IMNs, supraclavicular (SCV), and infraclavicular (ICV) nodes, with or without the axillary nodes, each contributing to a complex target requiring a more complicated treatment plan than breast-only treatment. As discussed in the prior section, the chest wall is a concave structure that wraps around the lung and anterior heart, two structures that are often partially irradiated to full dose with tangents. Furthermore, the SCV region lies anterior to the lung apex and is in close proximity to the brachial plexus (Fig 2). To treat the SCV region, a direct anterior portal prescribed to a fixed depth, usually 3 cm, is typically used in standard t r e a t m e n t planning. Madu and colleagues demonstrated that the SCV and ICV areas are often inadequately covered by this technique because of patient-to-patient variability in depth of the nodes, m In that study, the median m a x i m u m depth was 5.0 cm (range 3.9-8.3 cm) for the SCV and 5.6 cm (range 3.3-7.3 cm) for the ICV nodes. When the standard direct field technique was applied, only 93% of the SCV and 88% of the ICV nodes were covered by the 90% isodose surface. When a conformal technique was applied, coverage was 100% for both nodal regions. This study emphasizes the dosimetric gains that can be made with accurate target definition and conformal planning. Similarly, the IMNs need to be contoured (Fig 3). The IMNs lie deep to the chest wall on the
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endothoracic fascia in interspaces 1-6, between the costal cartilages. Because the majority of the IMNs are located in the upper chain, and inclusion of the lower chain in the radiotherapy field could increase the risk of cardiac toxicity, a compromise often occurs when only the superior half of the IMN chain is treated2 ~ For purposes of this discussion, the IMN target will be defined as interspaces 1-3. For left-sided tumors, the anterior and superior portions of the heart, as well as the superior lung, are at risk for radiation exposure depending on the t r e a t m e n t technique used. Recently, a comprehensive study of seven modern, postmastectomy treatments demonstrated that no single, standard technique combines the best chest wall and IMN coverage with optimal sparing of the heart and lungs. 2~ However, the partially wide tangent fields (PWTF) technique provided the best balance between target coverage and normal tissue sparing2 ~ This plan was generated with the explicit use of the 3D planning system to identify and treat the IMNs in the first three intercostal spaces. Medial and lateral coplanar tangents using 6 mV photons were used. The heart was identified and excluded from the inferior portion of the tangents using shaped cerrobend blocks. When the IMN volume and heart overlapped, preference was given to shielding the heart. The inferior medial chest wall (heart shadow) was then treated with supplemental electrons (6 or 9 MeV). There are, however, limitations with this approach. With PWTF, the superior part of the field irradiates a significant section of lung to full dose. The amount of lung receiving full dose is less in left-sided than in right-sided tumors, because the heart and great vessels occupy space in the left thorax, but the heart and vasculature are also potentially at risk. As the depth to the IMNs increases, the width of the tangents required also increases, thereby increasing the volume of lung irradiated. This also places the medial aspect of the contralateral breast at risk for direct radiation exposure. In cases in which the heart abuts the chest wall, the PWTF technique preferentially blocks the heart and thus compromises coverage of the chest wall (Fig 4). In these scenarios, alternative techniques would be required to satisfy full coverage to the chest wall and regional nodes while limiting dose to normal structures. 3D t r e a t m e n t planning provides the tools needed to improve target coverage
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Figure 4. Yellow arrows indicate the regions of underdosing, with the use of a complete heart block in the partially wide tangent technique.
while sparing normal tissues. This type of sophisticated planning, however, depends on the experience of the dosimetrist and the time allowed for planning. In a busy clinic, the latter will often be the limiting factor in producing a fully optimized plan. F u r t h e r m o r e , m a n y 3D t r e a t m e n t plans are complicated. Plans designed to treat the I M N conformally may involve multiple fields or segments that require multiple field matches between photons and electrons. Multiple matches are difficult to treat as well as to verify, and m a y result in additional machine time and increase the risk of matchline fibrosis. The complexity of 3D planning and delivery makes I M R T based on inverse planning attractive, because standard planning limitations m a y be reduced t h r o u g h the use of inverse planning. A u t o m a t e d I M R T treatm e n t delivery may potentially help to improve t r e a t m e n t delivery efficiency.
Clinical Considerations f o r I M R T Although c o n t e m p o r a r y radiotherapy techniques have substantially reduced the volume of heart exposed to radiation c o m p a r e d to earlier field a r r a n g e m e n t s , 2~ CT-based studies still demonstrate delivery of high doses to small regions of the left anterior heart and coronary vasculature when tangential irradiation is used. 2s,24 This
Figure 5. Nine equispaced axial beams were used for the IMRT technique: (A) Each beam is divided into 1 • 1 cm beamlets of varying intensities, determined by the optimization algorithm; the chest wall (violet), internal mammary nodes (red), heart (yellow), and spinal cord (green) are shown. (B) Isodose distributions in the axial and (C) sagittal planes. The internal mammary nodes (circled) are treated conformally with this technique.
Figure 6. Catheters delineate the clinically defined borders. Pink arrows point to the catheters placed at interspaces 1-3, the region of the internal mammary node target. The blue arrows point to the catheters placed at the medial, lateral, and inferior borders of the chest wall. The head of the clavicle (star) serves as the superior border. A catheter is also placed on the surgical scar (circled).
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could result in an increase in cardiac events in patients treated for left-sided cancers. Paszat and colleagues reported the relative risk for fatal myocardial infarction in women irradiated for left-sided breast cancer to be 1.17, and found that the risk increased 2-fold in patients under the age of 60 years. 25 The risk of pericarditis is also increased following radiotherapy to the breast/ chest wall and regional nodes, with a recent series reporting a 10% incidence of transient pericarditis following comprehensive left-sided treatment. 26 The use of radiotherapy following adjuvant chemotherapy, specifically, with agents that are known cardiotoxins, is a significant concern. Almost all women in this country with nodepositive breast cancer will receive doxorubicin at some point in their treatment course, and trastuzumab, previously used for metastatic disease, is now being aggressively tested as adjuvant therapy; each is known to cause cardiac dysfunction secondary to cardiomyopathy. Thus, the potential additive cardiac toxicities of systemic therapy and radiotherapy must be considered, and techniques that further decrease cardiac exposure to a level below that achieved with current treatment techniques are essential. This task will be difficult when including the IMN region in the target coverage because of the close proximity of these nodes to the heart. In addition, reducing heart dose must be accomplished without compromising target coverage and local control. With the large number of degrees of freedom possible with IMRT, intensity-modulated treatment has the potential to achieve both full-target coverage and reduction of cardiac and lung exposure, as presented below.
Data Few centers have utilized IMRT for breast/chest wall and regional irradiation. A planning study performed on one patient from the University of Wisconsin--Madison demonstrated improvements in breast, IMN, left lung, and heart dosevolume histograms (DVJqs) with IMRT (via tomotherapy) and inverse planning compared to standard tangents matched to a separate mixedbeam field for IMN coveraged 7 However, doses to the spinal cord and contralateral breast, and normal soft tissues were not reported. A pilot study performed at the University of Michigan investigated the use of IMRT for locoregional irradia-
Table 1. IMRT Plans Versus PWTF Standard Technique IMRT
CW Dmin(Gy) IMN Dmin(Gy) Heart V30(%) Heart NTCP Left lung mean dose
43.7 43.8 0.12 0.04
(1.1) (1.7) (0.2) (0.03)
9.5 (2.5)
PWTF
P value
31.2 (16.5) 29.1 (13.0) 0.40 (0.7) 0.08 (0.07)
.04 .003 .28 .41
17.6 (3.3)
<.0001
tiond ~ Comprehensive target (chest wall, IMNs, SCV and ICV nodes) and normal tissue definition (heart, great vessels of the chest, bilateral lungs, contralateral breast, spinal cord, left brachial plexus, and normal soft tissues) were undertaken. An in-house optimization system allowed for flexible cost-function specification, with inclusion of normal tissue complication probabilities and the ability to vary costs steeply by assigning higher power functions. With the use of a general axial IMRT 9-beam arrangement (Fig 5A-C), considerable improvements were found with regard to breast homogeneity, IMN coverage, and reduction in heart and lung doses compared to optimal conventional techniques, while limiting doses to all other normal tissues to clinically acceptable levels. The IMRT plans resulted in more uniform chest wall coverage than the PWTF standard technique, with a significant difference in the minimum dose (Drain) (Table 1). The IMRT plans also matched the low doses to the heart and normal tissue complication probabilities (NTCPs) for ischemic heart disease achieved using PWTF. While maintaining excellent chest wall coverage, and minimizing heart NTCP, IMRT improved the IMN coverage for all patients studied. Average IMN Dmin was 43.8 Gy (SD 1.7) for IMRT compared to 29.1 Gy (SD 13.0) for PWTF (P = .003). Left lung mean doses were also significantly lower than those for PWTF. Contralateral breast doses for IMRT were limited to 0.8-2.5 Gy. Doses to the great vessels, brachial plexus, and cord were all minimized (Fig 5B).
Considerations in Inverse Planning and Delivery of IMRT in Breast Cancer Patients Inverse planning IMRT for locoregional treatment requires careful target and normal tissue delineation in an organ site treated traditionally
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and having clinically defined borders. Cost-function specification is crucial yet complex given the history of local control and limited complications associated with the tangential technique. Tangential irradiation is the standard technique against which IMRT should and will be compared.
Targets and Organs at Risk Target and normal tissue definition are essential, because the optimization algorithm uses these volumes to determine beamlet intensity patterns. The target must be both defined and drawn consistently. A jagged edge in the contour may result in a highintensity beamlet that increases the dose to a nearby critical structure. Therefore, contours must be drawn with meticulous care and greater precision than with 3D treatment planning. Defining the chest wall/breast is not a straightforward task. Anatomically, the breast extends from approximately the second to the seventh intercostal spaces. Medially, the breast can extend to the sternum, while laterally it ends anterior to the trapezius, generally to the anterior axillary line. The chest wall includes the ribs, intercostal muscles, and the serratus anterior muscle. The clinically defined borders, however, are generally the clavicular head superiorly, 1-2 cm below the contralateral i n f r a m a m m a r y fold inferiorly, the midline medially, and the midaxillary line laterally (Fig 6). A reasonable approach in determining the tissues at risk for I M R T planning is to outline the tissues irradiated in the 95% isodose line when the clinical borders of tangents are applied. This ensures, at least, coverage of the traditional target volume. However, if this approach is used, one should be aware that tissue at the lateral edge of this volume may overestimate the actual extent of the target. Clinical j u d g m e n t is required to determine the extent of the chest wall/breast at risk. The SCV, ICV, and IMNs also need to be contoured for locoregional treatment. Like the chest wall, the SCV and ICV areas have traditionally been clinically defined. In a CT-based study, Madu and colleagues 19 determined the anatomical boundaries of the SCV and ICV fossae. For I M R T planning, the anatomical boundaries specified in this article provide guidance for contouring this region. Figure 2 shows the SCV and ICV volumes. For definition, the IMN region con-
sists of interspaces 1-3, as previously described (Fig 3). Although these nodes are often not visible on CT scans, the adjacent IMN vessels provide a reliable guide to their location. A conservative approach in contouring this region is to extend the target 1 cm laterally to the vessels, 1 cm medially or to the edge of the sternum, posteriorly to the visceral pleura, and anteriorly to the intercostal fascia. All normal tissues traversed by a b e a m must be outlined for IMRT planning. The heart and lungs, of course, need to be defined. Contouring the cardiac silhouette is straightforward and the lungs can be autocontoured by most planning systems. However, structures not typically outlined in standard or 3D planning need to be contoured for IMRT planning. If these structures are neither outlined nor assigned a cost function, high doses can be delivered to normal structures in an attempt to achieve a clinical goal, such as minimum target dose. Thus, the great vessels above the heart, contralateral lung, spinal cord, and the left brachial plexus in the supraclavicular fossa region need to be defined. Also, the arm and posterior thorax may need to be defined, depending on the chosen beam arrangement.
Cost-Function Specification for Breast IMRT For inverse planning, clinical goals are expressed in a mathematical term called the "cost function." If the cost function is defined correctly, the inverse planning algorithm will iterate to determine beam parameters automatically that minimize the cost function, thereby producing the desired dose distribution. The desired outcome must be expressed for all targets and normal tissues within the irradiated volume. However, the objectives must be reasonable and allow for trade-offs between normal tissues and target goals. For example, 5 beams arranged 180~ around the breast, with optimization specifying a desired dose to the chest wall of 50 Gy and 0 Gy to the lung, contralateral breast, and heart, will likely render an unsuccessful inverse plan that will either be aborted or result in an unacceptable dose distribution. In this situation, the potential advantages of IMRT will not be realized, because the cost function was not allowed to make trade-offs between target and normal tissues. A more reasonable approach to specifying cost functions for breast IMRT may be to use either toler-
I M R T Treatment of Breast Cancer
ance doses of normal tissues from data observed in other organ sites (eg, lung) or clinically acceptable dose and volume data from a standard plan, such as tangents, based on established rates of local control and complications, as discussed below. A comprehensive dosimetric study by Pierce and colleagues revealed that standard tangents deliver 95% of the prescribed dose to approximately 90% of the chest wall volume outlined on CT scans. 21 The dose deficit occurred at the edge of the tangent fields in the medial or lateral parts of the chest wall. This study demonstrated that prescribing to a point, as is often done for standard breast planning, does not ensure that the entire target receives full dose. To achieve full dose throughout the target, one must define the planning criteria and/or inverse planning cost function, so that high priority is given to target coverage (in order to avoid areas of underdosing). This kind of rigorous target coverage demand will likely result in delivery of (at least) the prescribed dose throughout the chest wall, giving more dose to the edges of the target volume than is usually delivered with standard tangents. In a sense, dose escalation occurs unintentionally as a consequence of cost-function specification and the optimization process. A clinical approach to cost-function specification can also be utilized for normal tissues. For example, the contralateral breast dose averages between 0.5 and 2.5 Gy following standard tangents, with doses up to 10 Gy medially. 2s Based on these data, it is clear that the contralateral breast has traditionally received a small but finite amount of radiation. Therefore, a cost function specifying 0 dose to the opposite breast may not be practical when currently used and accepted t r e a t m e n t techniques have never achieved this stringent criterion. Some investigators may argue that specifying 0 dose to the contralateral breast will ensure even lower doses than typically observed with tangents. This may or may not be true, depending on the priorities set for other normal tissues and the details of the cost function. If 0 dose to the contralateral breast is achieved, it may be at the expense of a overdosing another normal tissue structure or underdosing the target. Based upon the clinical experience with tangents, allowing limited dose to the opposite breast no greater than that obtained with tangential irradiation appears reasonable if it is required to achieve optimal target coverage and
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sparing of other normal tissues. This clinical choice should be acceptable in the general population, because breast irradiation has not been associated with an increase in contralateral breast cancers compared to nonirradiated (surgical) controls in randomized clinical trials. 29-3~ However, this may not be acceptable in patients with a genetic predisposition to breast cancer, and clinical judgment must be exercised when treating this patient subgroup. 33 Pneumonitis following tangential irradiation occurs in less than 5% of patients treated with tangential fields. 2 This suggests that irradiating the rind of lung within the tangent beams is clinically acceptable. The intentional inclusion of the IMN, however, increases the amount of lung in the field and can result in higher pneumonitis rates in some patient groups. ~4 Therefore, cost-function specification for lung is crucial for maintenance of clinically acceptable rates of pneumonitis. As discussed for the contralateral breast, it is extremely unlikely that 0 dose to the lung can be achieved with a 0 dose cost-function constraint. Again, other clinical goals may be compromised. In addition, allowing the anterior part of the lung (typically irradiated in tangents) to receive full dose will likely result in a tangent-like treatment plan. If improvement on tangents is desired, then utilization of lung complication data may be a reasonable option. For example, limiting the volume receiving 20 Gy or using mean lung dose may be acceptable approaches. 35 An alternative approach may be to utilize normal tissue complication data. However, commercial inverse planning systems often do not allow optimization based on biological models. At the University of Michigan, the in-house system allows both DVHand NTCP-based cost functions. Figure 5 depicts the isodose distributions after optimization, with the goal of a 0% lung complication probability, using previously published NTCP-model parameters obtained from breast and lung cancer patients. 36 As previously discussed, for left-sided cancers, the anterior heart may be exposed to high doses following the tangential irradiation technique. IMRT and inverse planning may decrease cardiac irradiation, but cost-function specification is required. However, there are very few clinical data on dose versus cardiac complications; therefore, cardiac cost-function specification becomes problematic. One approach is to use the available dosevolume cardiac data. It is known that the heart
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D V H profile of tangents produces low complication rates. Thus, a D V H - b a s e d cost function, which attempts to m a t c h the h e a r t DVH profile of tangents, may be a viable option. However, the cost function will not dictate where the dose is deposited within the heart. An I M R T plan m a y produce a D V H similar to that obtained with tangents, but the highest dose could be delivered anywhere in the heart, depending on the cost function specified for other structures. Once again, clinical d a t a m a y be beneficial. For example, d a t a from mantle field irradiation indicate that cardiac doses less than 30 Gy produce few cardiac events, z7 Using a dosebased function limiting radiation to the heart to 30 Gy, in addition to a DVH-based cost function based upon tangential irradiation, m a y be a good approach. A n o t h e r approach would be to use a biological model, such as the relative seriality model of Gagliardi et al, 3~ to predict probabilities of cardiac ischemia. Inclusion of biological models in the cost function for I M R T optimization is currently not feasible with m a n y commercially available inverse planning systems or methods. W h e n I M R T is used, radiation can be delivered to soft tissues outside the breast in areas that are typically not irradiated, governed by the planning approach and details of the various cost-functions. The long-term effect of irradiating tissues that are typically not i r r a d i a t e d with s t a n d a r d techniques is not known. F u r t h e r m o r e , breast cancer patients generally experience long survival time and can therefore be at risk for development of late complications. Thus, an I M R T plan that irradiates tissues not typically included in t a n g e n t fields is less desirable from this perspective. At the same time, I M R T techniques have the potential to improve target homogeneity and spare specified n o r m a l tissues. Despite the use of computer-assisted optimization, d e t e r m i n a t i o n of the optimal plan for each patient is still based on clinical j u d g m e n t not only for costfunction specification but also for weighing the risks of irradiating the unknown against the benefits of delivering homogeneous t r e a t m e n t and reducing exposure to known vital structures.
Future Directions I M R T and inverse p l a n n i n g m a y r e s u l t in an o p t i m a l p l a n t h a t satisfies all clinical c r i t e r i a . However, t h e s e p o t e n t i a l gains will only be realized with a c c u r a t e delivery of the o p t i m i z e d plan. U n f o r t u n a t e l y , o p t i m i z a t i o n is c u r r e n t l y per-
f o r m e d on static C T scans c a p t u r e d at one point in time, yet the chest wall is a c o n s t a n t l y moving t a r g e t d u r i n g r a d i a t i o n delivery. I n c o r p o r a t i o n of chest wall m o t i o n into o p t i m i z a t i o n algor i t h m s 39,4~ and s u s p e n s i o n o f the b r e a t h i n g cycle d u r i n g I M R T delivery4~ a r e c u r r e n t topics of investigation. U n t i l (1) s e t u p accuracy a n d o r g a n m o t i o n issues are r o b u s t l y h a n d l e d , (2) t a r g e t volumes are m o r e carefully defined, and (3) bett e r clinical trade-offs and clinical d a t a a r e inc l u d e d in the d e r i v a t i o n o f the inverse p l a n n i n g cost function, the use of I M R T for t r e a t m e n t of the b r e a s t / c h e s t wall a n d r e g i o n a l nodes should be l i m i t e d to carefully d e s i g n e d clinical trials.
Acknowledgments W e would like to t h a n k Robin M a r s h a n d J e f f r e y R a d a w s k i for t h e i r assistance in the p r e p a r a t i o n of this m a n u s c r i p t .
References 1. Clarke D, Martinez A, Cox RS, et al: Analysis of cosmetic results and complications in patients with stage I and II breast cancer treated by biopsy and irradiation. Int J Radiat Oncol Biol Phys 9:1807-1813, 1983 2. Pierce SM, Recht A, Lingos TI, et al: Long-term radiation complications following conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 23:915-923, 1992 3. Gray JR, McCormick B, Cox L, et al: Primary breast irradiation in large-breasted or hea'rT women: Analysis of cosmetic outcome. Int J Radiat Oncol Biol Phys 21:347354, 1991 4. Bortfeld T: Optimized planning using physical objectives and constraints. Semin Radiat Oncol 9:20-34, 1999 5. ArefA, Thornton D, YoussefE, et al: Dosimetric improvements following 3D planning of tangential breast irradiation. Int J Radiat Oncol Biol Phys 48:1569-1574, 2000 6. Evans PM, Donovan EM, Partridge M, et al: The delivery of intensity modulated radiotherapy to the breast using multiple static fields. Radiother Oncol 57:79-89, 2000 7. Zackrisson B, Arevarn M, Karlsson M, et al: Optimized MLC-beam arrangements for tangential breast irradiation. Radiother Oncol 54:209-212, 2000 8. Lo YC, Yasuda G, Fitzgerald TJ, et al: Intensity modulation for breast treatment using static multi-leaf collimnators. Int J Radiat Oncol Biol Phys 46:187-194, 2000 9. van Asselen B, Raaijmakers CP, Hofman P, et al: An improved breast irradiation technique using three-dimensional geometrical information and intensity modulation. Radiother Oncol 58:341-347, 2001 10. Donovan EM,Johnson U, Shentall G, et ah Evaluation of compensation in breast radiotherapy: A planning study using multiple static fields. Int J Radiat Oncol Biol Phys 46:671-679, 2000
I M R T Treatment of Breast Cancer
11. Kestin LL, Sharpe MB, Frazier RC, et ah Intensity modulation to improve dose uniformity with tangential breast radiotherapy: Initial clinical experience. IntJ Radiat Oncol Biol Phys 48:1559-1568, 2000 12. Chang SX, Deschesne KM, Cullip TJ, et ah A comparison of different intensity modulation treatment techniques for tangential breast irradiation. Int J Radiat Oncol Biol Phys 45:1305-1314, 1999 13. Hong L, Hunt M, Chui C, et al: Intensity-modulated tangential beam irradiation of the intact breast. Int J Radiat Oncol Biol Phys 44:1155-1164, 1999 14. LiJG, Williams SS, Goffinet DR, et ah Breast-conserving radiation therapy using cmnbined electron and intensitymodulated radiotherapy technique. Radiother Oncol 56: 65-71, 2000 15. Landau D, Adams EJ, Webb S, et al: Cardiac avoidance in breast radiotherapy: A comparison of simple shielding techniques with intensity-modulated radiotherapy. Radiother Oncol 60:247-255, 2001 16. RagazJ, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. NEJM 337:956-962, 1997 17. Overgaard M, Hansen PS, OvergaardJ, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. NEJM 337:949-955, 1997 18. Overgaard M, Jensen MB, OvergaardJ, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 353:1641-1648, 1999 19. Madu CN, Quint DJ, Normolle DP, et ah Definition of the supraclavieular and infraclavicular nodes: Implications for three-dimensional CT-based conformal radiation therapy. Radiology 221:333-339, 2001 20. Marks LB, Hebert ME, Bentel G, et al: To treat or not to treat the internal mammary nodes: A possible compromise. Int J Radiat Oncol Biol Phys 29:903-909, 1994 21. Pierce L, Butler J, Martel K, et al: Post-mastectomy radiotherapy of the chest wall: Dosimetric comparison of comnmn techniques. Int J Radiat Oncol Biol Phys 52: 1220-1230, 2002 22. Nixon AJ, Manola J, Gelman R, et ah No long-term increase in cardiac-related mortality after breast-conserving surgeiT and radiation therapy using modern techniques. J Clin Oncol 16:1374-1379, 1998 23. Fuller SA, HaybittleJL, Smith RE, et al: Cardiac doses in post-operative breast irradiation. Radiother Oncol 25:1924, 1992 24. Krueger EA, Fraass BF, McShan DL, et al: The potential gains for chest wall and regional nodal irradiation using intensity modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys 51:123, 2001 (abstr, suppl 1) 25. Paszat LF, Mackillop WJ, Groome PA, et al: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and endresults cancer registries.J Clin Oncol 16:2625-2631, 1998 26. Hardenbergh PH, Munley MT, Bentel GC, et ah Cardiac perfusion changes in patients treated for breast cancer with radiation therapy and doxorubicin: Preliminary results. Int J Radiat Oncol Biol Phys 49:1023-1028, 2001
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27. Reckwerdt PJ, Olivera G, Shepard DM, et al: Case Studies in Tomotherapy Optimization: Breast, Prostate, Mesothelioma, and Nasopharyngeal treatments. Heidelberg, Germany, Proceedings of the XV International Conference on Computers in Radiation Therapy, 2000 28. Fraass BA, Roberson PL, Lichter AS, et al: Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 11:485-497, 1985 29. Veronesi U, Banff A, Salvadori B, et al: Breast conservation is the treatment of choice in small breast cancer: Long-term results of a randomized trial. Eur J Cancer 26:668-670, 1990 30. Fisher B, Anderson S: Conservative surgery for the management of invasive and noninvasive carcinoma of the breast: NSABP trials. National Surgical Adjuvant Breast and Bmvel Project. WorldJ Surg 18:63-69, 1994 31. Jacobson JA, Danforth DN, Cowan KH, et al: Ten-year results of a comparison of conservation with nlastectomy in the treatment of stage I and II breast cancer. NEJM 332:907-911, 1995 32. Arriagada R, Le MG, Rochard L, et al: Conservative treatment versus mastectomy in early breast cancer: Patterns of failure with 15 )rears of follow-up data. Institut Gustave-Roussy Breast Cancer Group. J Clin Oncol 14: 1558-i564, 1996 33. Pierce LJ, Strawderman M, Narod SA, et al: Effect of radiotherapy after breast-conserving treatn~mnt in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 18:3360-3369, 2000 34. Marks LB, Fan M, Clough R, et al: Radiation (RT)induced pneuinonitis following tangential breast/chestwall irradiation. Int J Radiat Oncol Biol Phys 48:294-295, 2000 35. Kwa SL, LebesqueJV, TheuwsJC, et al: Radiation pneumonitis as a function of mean lung dose: An analysis of pooled data of 540 patients. Int J Radiat Oncol Biol Phys 42:1-9, 1998 36. Martel MK, Ten Haken RK, Hazuka MB, et al: Dosevolume histogram and 3-D treatment planning evaluation of patients with pneumonitis. IntJ Radiat Oncol Biol Phys 28:575-581, 1994 37. ttancock SL, Tucker MA, Hoppe RT, et al: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270:1949-1955, 1993 38. Gagliardi G, Lax I, Ottolenghi A, et al: Long-term cardiac mortality after radiotherapy of breast cancer: Application of the relative seriality model. Br J Radiol 69:839-846, 1996 39. LiJG, Xing L: Inverse planning incorporating organ motion. Med Phys 27:1573-1578, 2000 40. McShan DL, Ten Haken RK, Kessler ML: Radiotherapy plan optimization accounting for set-up and motion uncertainty using a multiple instance geomtry approximation. Proceedings of the European Society fi-~rTherapeutic Radiology and Oncology, Seville, Spain, September 2001 41. StrombergJS, Sharpe MB, Kim LH, et al: Active breathing control (ABC) for Hodgkin's disease: Reduction in normal tissue irradiation with deep inspiration and implications for treatment. Int J Radiat Oncol Biol Phys 48:797-806, 2000
to the patient. Thus, IMRT has the potential to improve target coverage and reduce inhomogeneities observed within the breast (and regional lymph nodes) that are obtained with standard plans. Furthermore, IMRT may be able to reduce doses delivered to the heart and lungs, and may potentially minimize further the probability of complications from radiotherapy. Copyright 2002, Elsevier Science (USA). Aft rights reserved.
I ntensity-modulated radiation therapy (IMRT) .is a general term referring to any radiation technique that utilizes variable beam intensities across an irradiated volume. In recent years, IMRT has referred to intensity modulation via segmental, mini- or nmltivane, or dynamic multileaf collimator (MLC) delivery combined with inverse planning, as evidenced by the articles in this edition o f Seminars in Radiation Oncology. However, IMRT techniques used in breast cancer patients vary widely. Investigators often use the term "IMRT" to describe a specific treatment for breast irradiation, although the goals, optimization approaches, and delivery techniques can be quite different from study to study, thereby making comparisons of IMRT studies difficult. In this review, we attempt to clarify the goals, optimization approaches, and delivery techniques used in published breast IMRT studies. IMRT for the breast alone is discussed separately from that for the breast/chest wall and regional nodes, because clear differences exist between the two subjects. We highlight the clinical and technical aspects associated with IMRT and how these relate to our knowledge of standard treatment techniques for breast cancer patients. Finally, we
discuss the clinical considerations involved with the specific use of inverse planning for IMRT plan optimization.
From the Department of Radiation Oncology, University of Michigan, Ann Arbor, MI. Address reprint requests to Lori J. Pierce, MD, Department of Radiation Oncology, University of Michigan School of Medicine, 1500 E. Medical Center Drive, UHB2C-490, Box 0010, Ann Arbor, MI 48109. E-maib [email protected]. Copyright 2002, Elsevier Science (USA). All @ t s reserved. 1053-4296/02/1203-0007535.00/0 doi:l O.1053/srao.2002.32468 950
Breast-Only Treatment Rationale The breast has been successfully treated with tangential beams for many years, resulting in excellent local control rates, low rates of pulmonary and cardiac complications, and excellent cosmesis in the majority of patients. 1,2 For these reasons, many question a role for IMRT in breast-only treatment. However, standard tangents have several limitations. First, dose homogeneity across the entire breast is difficult to achieve because of the complicated geometry of the breast. Dose inhomogeneities typically exist at the entrance and exit points, the nipple, and in the most superior and inferior portions of fields (Fig 1A and B) when the breast is treated with tangents. Use of wedges and lung inhomogeneity correction reduces the dose inhomogeneity, but a fully homogenous dose distribution across the entire field is difficult to achieve with flat (unmodulated) tangential beams. These dose inhomogeneities are further exaggerated in largebreasted women, in whom the inhomogeneities have been associated with less favorable cosmetic results. 3 The standard tangent technique invariably irradiates a section of lung and sometimes a portion of the heart to full dose for left-sided lesions (Fig 1A). Furthermore, reduction in heart and lung exposure using fiat, unmodulated
Seminars in Radiation Oncology, Vol 12, No 3 (July), 2002: pp 250-259
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/
a
-, - .
Figure 2. Supraclavicular region: SCV, supraclavicular; ICV, infraclavicular; LBP, left brachial plexus.
I M R T is used. In left-sided cancers, the heart can also potentially be spared. Thus, although the use of standard tangents has been successful, there is potential for further improvement with IMRT.
Data Multiple approaches utilizing compensators or I M R T delivery of modulated intensity beams have been applied to the t r e a t m e n t of the breast. A common method for decreasing the dose inhomogeneity in the breast that is observed with standard wedge techniques makes use of mechanical compensators. 5 The t r e a t m e n t planning process for the design of these physical compensators utilizes 3-dimensional (3D) tools during an iterative optimization process. Recently, a segmental multileaf collimator technique (sMLC) has also been used to improve dose homogeneity. 6-8 Figure 1. Typical isodose distributions for standard tangents. (A) Axial view showing hot spots in yellow; (B) sagittal view showing the inhomogeneity at the superior and inferior most regions of the breast. beams is difficult to achieve because of the concave geometry of the breast and underlying chest wall. Thus, inclusion of lung and possible heart tissue in the radiotherapy field has been a known limitation of tangential irradiation. However, with the development of IMRT, further reduction in heart and lung doses can now potentially be achieved. In fact, the benefit of IMRT has been best described for concave structures, such as the chest wall, which wraps around the lung and anterior portion of the heart. 4 It may be possible to minimize the section of lung that is irradiated to full dose by tangents when
Figure 3. Internal mammary nodes (IMN) lie deep to the chest wall (CW) along the endothoracic fascia. The heart is outlined in yellow.
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The sMLC technique combines several discrete fields of radiation in order to modulate the intensity across the treatment volume. Much like the design of physical compensators, a planner utilizes 3D treatment planning tools and calculations for optimization of the multileaf collimator (MLC) segments. Others have used equivalent path length maps and transit dosimetry information from electronic portal imaging devices (EPIDs) to determine areas of dose inhomogeneity in the breast. 9,1~ The same iterative process for the addition of segments is performed to eliminate areas of over- and underdosing. The William Beaumont group recently published data on an additional technique, whereby segments were designed from isodose surfaces calculated from an open tangent field, ~l and each segment weight was then optimized using a computer algorithm. Although this automates the treatment planning process, the optimization described did not include constraints for normal tissues, such as heart and lung, in the treatment volume. Few investigators have used inverse planning with optimization parameters (ie, cost functions that specify normal tissue constraints). Chang and colleagues from the University of North Carolina performed a study comparing different intensity modulation techniques for tangential breast irradiation. ~2 An in-house dose-gradient algorithm was used to optimize segments such that maximum homogeneity in the breast was achieved with a dose limit set for nearby critical structures. Dose measurements performed in a phantom trial confirmed that less dose was delivered to the contralateral breast with sMLC compared to the standard wedge technique. Other normal structure doses were not reported. The first comprehensive cost-function specification published for breast-only treatment was described by the group from Memorial Sloan-Kettering Cancer Center. t3 Similar to the studies previously discussed, the target volume was the breast only. Dose homogeneity within the breast was a desired result. Unlike the other studies, however, the automated algorithm used in optimizing intensity profiles included constraints to multiple normal structures, specifically, ipsilateral lung, heart, contralateral breast, and surrounding soft tissue. Modest dose reductions of these normal structures and improvement in target homogeneity were observed in 10 patients. The IMRT plans consisted of 2 beams in a tan-
gential arrangement delivered with dynamic multileaf collimators (dMLC). Other groups have expanded from a 2-field beam arrangement to allow more degrees of freedom and perhaps achieve more gains with IMRT. Li and colleagues from Stanford University were among the first to incorporate additional beams and electrons in breast IMRT planning? 4 More recently, Landau and colleagues developed three IMRT techniques: a 2- and 4-field tangent-like beam arrangement, and a 6-field arc plan. ix Similar to the Memorial Sloan-Kettering study, all IMRT plans were generated using a comprehensive cost function. The IMRT techniques were compared to standard techniques, with and without heart blocking ("Pb block"). Although the Pb block plan resulted in less heart volume receiving 60% of the prescription dose compared to the IMRT techniques (Pb block, 0.1%, vs 2- to 4-field IMRT, 2.2%, vs 6-field IMRT, 7.2%), the IMRT techniques resulted in better target coverage, with a 65% minimum target dose with the Pb block plan compared to 92%, 94%, and 92% minimum target doses with 2-, 4-, and 6-field plans, respectively. However, the 4- and 6-field IMRT techniques delivered higher mean doses to the contralateral breast and lung compared to standard techniques. Thus, in this study, although the additional beams allowed for more degrees of freedom and perhaps achieved more of the specified clinical goals, these gains were tempered by the low doses of radiation delivered to regions not typically exposed using more standard techniques. This trade-off is discussed further in later sections.
Breast/Chest Wall and Regional Treatment Rationale The rationale for using IMRT for locoregional irradiation is arguably stronger than for breastonly treatment. Comprehensive locoregional irradiation includes treatment of the breast/chest wall, supraclavicular, infraclavicular, and internal mammary nodes (IMNs) (with or without axillary irradiation). Three recent randomized trials have shown a significant advantage in disease-specific and overall survival following comprehensive locoregional postmastectomy treatment. 16-18 Based on these and other studies, a
IMRT Treatment of Breast Cancer
National Institutes of Health (NIH) consensus panel recommended locoregional postmastectomy irradiation in patients with 4 or more positive axillary lymph nodes and/or T3 and T4 lesions. However, concern exists regarding the potential for increased heart exposure with inclusion of the IMNs in the target volume. This concern is amplified by the fact that a majority of these patients at high risk for distant dissemination will likely receive doxorubicin and possibly trastuzumab, two potentially cardiotoxic agents. Therefore, the use of I M R T in comprehensive locoregional therapy is justified, if it can be shown to further improve target homogeneity compared to standard techniques, and further reduce heart and lung exposure to doses lower than those currently achieved.
Technical Considerations for IMRT The targets for locoregional t r e a t m e n t include breast/chest wall, IMNs, supraclavicular (SCV), and infraclavicular (ICV) nodes, with or without the axillary nodes, each contributing to a complex target requiring a more complicated treatment plan than breast-only treatment. As discussed in the prior section, the chest wall is a concave structure that wraps around the lung and anterior heart, two structures that are often partially irradiated to full dose with tangents. Furthermore, the SCV region lies anterior to the lung apex and is in close proximity to the brachial plexus (Fig 2). To treat the SCV region, a direct anterior portal prescribed to a fixed depth, usually 3 cm, is typically used in standard t r e a t m e n t planning. Madu and colleagues demonstrated that the SCV and ICV areas are often inadequately covered by this technique because of patient-to-patient variability in depth of the nodes, m In that study, the median m a x i m u m depth was 5.0 cm (range 3.9-8.3 cm) for the SCV and 5.6 cm (range 3.3-7.3 cm) for the ICV nodes. When the standard direct field technique was applied, only 93% of the SCV and 88% of the ICV nodes were covered by the 90% isodose surface. When a conformal technique was applied, coverage was 100% for both nodal regions. This study emphasizes the dosimetric gains that can be made with accurate target definition and conformal planning. Similarly, the IMNs need to be contoured (Fig 3). The IMNs lie deep to the chest wall on the
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endothoracic fascia in interspaces 1-6, between the costal cartilages. Because the majority of the IMNs are located in the upper chain, and inclusion of the lower chain in the radiotherapy field could increase the risk of cardiac toxicity, a compromise often occurs when only the superior half of the IMN chain is treated2 ~ For purposes of this discussion, the IMN target will be defined as interspaces 1-3. For left-sided tumors, the anterior and superior portions of the heart, as well as the superior lung, are at risk for radiation exposure depending on the t r e a t m e n t technique used. Recently, a comprehensive study of seven modern, postmastectomy treatments demonstrated that no single, standard technique combines the best chest wall and IMN coverage with optimal sparing of the heart and lungs. 2~ However, the partially wide tangent fields (PWTF) technique provided the best balance between target coverage and normal tissue sparing2 ~ This plan was generated with the explicit use of the 3D planning system to identify and treat the IMNs in the first three intercostal spaces. Medial and lateral coplanar tangents using 6 mV photons were used. The heart was identified and excluded from the inferior portion of the tangents using shaped cerrobend blocks. When the IMN volume and heart overlapped, preference was given to shielding the heart. The inferior medial chest wall (heart shadow) was then treated with supplemental electrons (6 or 9 MeV). There are, however, limitations with this approach. With PWTF, the superior part of the field irradiates a significant section of lung to full dose. The amount of lung receiving full dose is less in left-sided than in right-sided tumors, because the heart and great vessels occupy space in the left thorax, but the heart and vasculature are also potentially at risk. As the depth to the IMNs increases, the width of the tangents required also increases, thereby increasing the volume of lung irradiated. This also places the medial aspect of the contralateral breast at risk for direct radiation exposure. In cases in which the heart abuts the chest wall, the PWTF technique preferentially blocks the heart and thus compromises coverage of the chest wall (Fig 4). In these scenarios, alternative techniques would be required to satisfy full coverage to the chest wall and regional nodes while limiting dose to normal structures. 3D t r e a t m e n t planning provides the tools needed to improve target coverage
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Figure 4. Yellow arrows indicate the regions of underdosing, with the use of a complete heart block in the partially wide tangent technique.
while sparing normal tissues. This type of sophisticated planning, however, depends on the experience of the dosimetrist and the time allowed for planning. In a busy clinic, the latter will often be the limiting factor in producing a fully optimized plan. F u r t h e r m o r e , m a n y 3D t r e a t m e n t plans are complicated. Plans designed to treat the I M N conformally may involve multiple fields or segments that require multiple field matches between photons and electrons. Multiple matches are difficult to treat as well as to verify, and m a y result in additional machine time and increase the risk of matchline fibrosis. The complexity of 3D planning and delivery makes I M R T based on inverse planning attractive, because standard planning limitations m a y be reduced t h r o u g h the use of inverse planning. A u t o m a t e d I M R T treatm e n t delivery may potentially help to improve t r e a t m e n t delivery efficiency.
Clinical Considerations f o r I M R T Although c o n t e m p o r a r y radiotherapy techniques have substantially reduced the volume of heart exposed to radiation c o m p a r e d to earlier field a r r a n g e m e n t s , 2~ CT-based studies still demonstrate delivery of high doses to small regions of the left anterior heart and coronary vasculature when tangential irradiation is used. 2s,24 This
Figure 5. Nine equispaced axial beams were used for the IMRT technique: (A) Each beam is divided into 1 • 1 cm beamlets of varying intensities, determined by the optimization algorithm; the chest wall (violet), internal mammary nodes (red), heart (yellow), and spinal cord (green) are shown. (B) Isodose distributions in the axial and (C) sagittal planes. The internal mammary nodes (circled) are treated conformally with this technique.
Figure 6. Catheters delineate the clinically defined borders. Pink arrows point to the catheters placed at interspaces 1-3, the region of the internal mammary node target. The blue arrows point to the catheters placed at the medial, lateral, and inferior borders of the chest wall. The head of the clavicle (star) serves as the superior border. A catheter is also placed on the surgical scar (circled).
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could result in an increase in cardiac events in patients treated for left-sided cancers. Paszat and colleagues reported the relative risk for fatal myocardial infarction in women irradiated for left-sided breast cancer to be 1.17, and found that the risk increased 2-fold in patients under the age of 60 years. 25 The risk of pericarditis is also increased following radiotherapy to the breast/ chest wall and regional nodes, with a recent series reporting a 10% incidence of transient pericarditis following comprehensive left-sided treatment. 26 The use of radiotherapy following adjuvant chemotherapy, specifically, with agents that are known cardiotoxins, is a significant concern. Almost all women in this country with nodepositive breast cancer will receive doxorubicin at some point in their treatment course, and trastuzumab, previously used for metastatic disease, is now being aggressively tested as adjuvant therapy; each is known to cause cardiac dysfunction secondary to cardiomyopathy. Thus, the potential additive cardiac toxicities of systemic therapy and radiotherapy must be considered, and techniques that further decrease cardiac exposure to a level below that achieved with current treatment techniques are essential. This task will be difficult when including the IMN region in the target coverage because of the close proximity of these nodes to the heart. In addition, reducing heart dose must be accomplished without compromising target coverage and local control. With the large number of degrees of freedom possible with IMRT, intensity-modulated treatment has the potential to achieve both full-target coverage and reduction of cardiac and lung exposure, as presented below.
Data Few centers have utilized IMRT for breast/chest wall and regional irradiation. A planning study performed on one patient from the University of Wisconsin--Madison demonstrated improvements in breast, IMN, left lung, and heart dosevolume histograms (DVJqs) with IMRT (via tomotherapy) and inverse planning compared to standard tangents matched to a separate mixedbeam field for IMN coveraged 7 However, doses to the spinal cord and contralateral breast, and normal soft tissues were not reported. A pilot study performed at the University of Michigan investigated the use of IMRT for locoregional irradia-
Table 1. IMRT Plans Versus PWTF Standard Technique IMRT
CW Dmin(Gy) IMN Dmin(Gy) Heart V30(%) Heart NTCP Left lung mean dose
43.7 43.8 0.12 0.04
(1.1) (1.7) (0.2) (0.03)
9.5 (2.5)
PWTF
P value
31.2 (16.5) 29.1 (13.0) 0.40 (0.7) 0.08 (0.07)
.04 .003 .28 .41
17.6 (3.3)
<.0001
tiond ~ Comprehensive target (chest wall, IMNs, SCV and ICV nodes) and normal tissue definition (heart, great vessels of the chest, bilateral lungs, contralateral breast, spinal cord, left brachial plexus, and normal soft tissues) were undertaken. An in-house optimization system allowed for flexible cost-function specification, with inclusion of normal tissue complication probabilities and the ability to vary costs steeply by assigning higher power functions. With the use of a general axial IMRT 9-beam arrangement (Fig 5A-C), considerable improvements were found with regard to breast homogeneity, IMN coverage, and reduction in heart and lung doses compared to optimal conventional techniques, while limiting doses to all other normal tissues to clinically acceptable levels. The IMRT plans resulted in more uniform chest wall coverage than the PWTF standard technique, with a significant difference in the minimum dose (Drain) (Table 1). The IMRT plans also matched the low doses to the heart and normal tissue complication probabilities (NTCPs) for ischemic heart disease achieved using PWTF. While maintaining excellent chest wall coverage, and minimizing heart NTCP, IMRT improved the IMN coverage for all patients studied. Average IMN Dmin was 43.8 Gy (SD 1.7) for IMRT compared to 29.1 Gy (SD 13.0) for PWTF (P = .003). Left lung mean doses were also significantly lower than those for PWTF. Contralateral breast doses for IMRT were limited to 0.8-2.5 Gy. Doses to the great vessels, brachial plexus, and cord were all minimized (Fig 5B).
Considerations in Inverse Planning and Delivery of IMRT in Breast Cancer Patients Inverse planning IMRT for locoregional treatment requires careful target and normal tissue delineation in an organ site treated traditionally
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and having clinically defined borders. Cost-function specification is crucial yet complex given the history of local control and limited complications associated with the tangential technique. Tangential irradiation is the standard technique against which IMRT should and will be compared.
Targets and Organs at Risk Target and normal tissue definition are essential, because the optimization algorithm uses these volumes to determine beamlet intensity patterns. The target must be both defined and drawn consistently. A jagged edge in the contour may result in a highintensity beamlet that increases the dose to a nearby critical structure. Therefore, contours must be drawn with meticulous care and greater precision than with 3D treatment planning. Defining the chest wall/breast is not a straightforward task. Anatomically, the breast extends from approximately the second to the seventh intercostal spaces. Medially, the breast can extend to the sternum, while laterally it ends anterior to the trapezius, generally to the anterior axillary line. The chest wall includes the ribs, intercostal muscles, and the serratus anterior muscle. The clinically defined borders, however, are generally the clavicular head superiorly, 1-2 cm below the contralateral i n f r a m a m m a r y fold inferiorly, the midline medially, and the midaxillary line laterally (Fig 6). A reasonable approach in determining the tissues at risk for I M R T planning is to outline the tissues irradiated in the 95% isodose line when the clinical borders of tangents are applied. This ensures, at least, coverage of the traditional target volume. However, if this approach is used, one should be aware that tissue at the lateral edge of this volume may overestimate the actual extent of the target. Clinical j u d g m e n t is required to determine the extent of the chest wall/breast at risk. The SCV, ICV, and IMNs also need to be contoured for locoregional treatment. Like the chest wall, the SCV and ICV areas have traditionally been clinically defined. In a CT-based study, Madu and colleagues 19 determined the anatomical boundaries of the SCV and ICV fossae. For I M R T planning, the anatomical boundaries specified in this article provide guidance for contouring this region. Figure 2 shows the SCV and ICV volumes. For definition, the IMN region con-
sists of interspaces 1-3, as previously described (Fig 3). Although these nodes are often not visible on CT scans, the adjacent IMN vessels provide a reliable guide to their location. A conservative approach in contouring this region is to extend the target 1 cm laterally to the vessels, 1 cm medially or to the edge of the sternum, posteriorly to the visceral pleura, and anteriorly to the intercostal fascia. All normal tissues traversed by a b e a m must be outlined for IMRT planning. The heart and lungs, of course, need to be defined. Contouring the cardiac silhouette is straightforward and the lungs can be autocontoured by most planning systems. However, structures not typically outlined in standard or 3D planning need to be contoured for IMRT planning. If these structures are neither outlined nor assigned a cost function, high doses can be delivered to normal structures in an attempt to achieve a clinical goal, such as minimum target dose. Thus, the great vessels above the heart, contralateral lung, spinal cord, and the left brachial plexus in the supraclavicular fossa region need to be defined. Also, the arm and posterior thorax may need to be defined, depending on the chosen beam arrangement.
Cost-Function Specification for Breast IMRT For inverse planning, clinical goals are expressed in a mathematical term called the "cost function." If the cost function is defined correctly, the inverse planning algorithm will iterate to determine beam parameters automatically that minimize the cost function, thereby producing the desired dose distribution. The desired outcome must be expressed for all targets and normal tissues within the irradiated volume. However, the objectives must be reasonable and allow for trade-offs between normal tissues and target goals. For example, 5 beams arranged 180~ around the breast, with optimization specifying a desired dose to the chest wall of 50 Gy and 0 Gy to the lung, contralateral breast, and heart, will likely render an unsuccessful inverse plan that will either be aborted or result in an unacceptable dose distribution. In this situation, the potential advantages of IMRT will not be realized, because the cost function was not allowed to make trade-offs between target and normal tissues. A more reasonable approach to specifying cost functions for breast IMRT may be to use either toler-
I M R T Treatment of Breast Cancer
ance doses of normal tissues from data observed in other organ sites (eg, lung) or clinically acceptable dose and volume data from a standard plan, such as tangents, based on established rates of local control and complications, as discussed below. A comprehensive dosimetric study by Pierce and colleagues revealed that standard tangents deliver 95% of the prescribed dose to approximately 90% of the chest wall volume outlined on CT scans. 21 The dose deficit occurred at the edge of the tangent fields in the medial or lateral parts of the chest wall. This study demonstrated that prescribing to a point, as is often done for standard breast planning, does not ensure that the entire target receives full dose. To achieve full dose throughout the target, one must define the planning criteria and/or inverse planning cost function, so that high priority is given to target coverage (in order to avoid areas of underdosing). This kind of rigorous target coverage demand will likely result in delivery of (at least) the prescribed dose throughout the chest wall, giving more dose to the edges of the target volume than is usually delivered with standard tangents. In a sense, dose escalation occurs unintentionally as a consequence of cost-function specification and the optimization process. A clinical approach to cost-function specification can also be utilized for normal tissues. For example, the contralateral breast dose averages between 0.5 and 2.5 Gy following standard tangents, with doses up to 10 Gy medially. 2s Based on these data, it is clear that the contralateral breast has traditionally received a small but finite amount of radiation. Therefore, a cost function specifying 0 dose to the opposite breast may not be practical when currently used and accepted t r e a t m e n t techniques have never achieved this stringent criterion. Some investigators may argue that specifying 0 dose to the contralateral breast will ensure even lower doses than typically observed with tangents. This may or may not be true, depending on the priorities set for other normal tissues and the details of the cost function. If 0 dose to the contralateral breast is achieved, it may be at the expense of a overdosing another normal tissue structure or underdosing the target. Based upon the clinical experience with tangents, allowing limited dose to the opposite breast no greater than that obtained with tangential irradiation appears reasonable if it is required to achieve optimal target coverage and
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sparing of other normal tissues. This clinical choice should be acceptable in the general population, because breast irradiation has not been associated with an increase in contralateral breast cancers compared to nonirradiated (surgical) controls in randomized clinical trials. 29-3~ However, this may not be acceptable in patients with a genetic predisposition to breast cancer, and clinical judgment must be exercised when treating this patient subgroup. 33 Pneumonitis following tangential irradiation occurs in less than 5% of patients treated with tangential fields. 2 This suggests that irradiating the rind of lung within the tangent beams is clinically acceptable. The intentional inclusion of the IMN, however, increases the amount of lung in the field and can result in higher pneumonitis rates in some patient groups. ~4 Therefore, cost-function specification for lung is crucial for maintenance of clinically acceptable rates of pneumonitis. As discussed for the contralateral breast, it is extremely unlikely that 0 dose to the lung can be achieved with a 0 dose cost-function constraint. Again, other clinical goals may be compromised. In addition, allowing the anterior part of the lung (typically irradiated in tangents) to receive full dose will likely result in a tangent-like treatment plan. If improvement on tangents is desired, then utilization of lung complication data may be a reasonable option. For example, limiting the volume receiving 20 Gy or using mean lung dose may be acceptable approaches. 35 An alternative approach may be to utilize normal tissue complication data. However, commercial inverse planning systems often do not allow optimization based on biological models. At the University of Michigan, the in-house system allows both DVHand NTCP-based cost functions. Figure 5 depicts the isodose distributions after optimization, with the goal of a 0% lung complication probability, using previously published NTCP-model parameters obtained from breast and lung cancer patients. 36 As previously discussed, for left-sided cancers, the anterior heart may be exposed to high doses following the tangential irradiation technique. IMRT and inverse planning may decrease cardiac irradiation, but cost-function specification is required. However, there are very few clinical data on dose versus cardiac complications; therefore, cardiac cost-function specification becomes problematic. One approach is to use the available dosevolume cardiac data. It is known that the heart
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Krueger, Fraass, and Pierce
D V H profile of tangents produces low complication rates. Thus, a D V H - b a s e d cost function, which attempts to m a t c h the h e a r t DVH profile of tangents, may be a viable option. However, the cost function will not dictate where the dose is deposited within the heart. An I M R T plan m a y produce a D V H similar to that obtained with tangents, but the highest dose could be delivered anywhere in the heart, depending on the cost function specified for other structures. Once again, clinical d a t a m a y be beneficial. For example, d a t a from mantle field irradiation indicate that cardiac doses less than 30 Gy produce few cardiac events, z7 Using a dosebased function limiting radiation to the heart to 30 Gy, in addition to a DVH-based cost function based upon tangential irradiation, m a y be a good approach. A n o t h e r approach would be to use a biological model, such as the relative seriality model of Gagliardi et al, 3~ to predict probabilities of cardiac ischemia. Inclusion of biological models in the cost function for I M R T optimization is currently not feasible with m a n y commercially available inverse planning systems or methods. W h e n I M R T is used, radiation can be delivered to soft tissues outside the breast in areas that are typically not irradiated, governed by the planning approach and details of the various cost-functions. The long-term effect of irradiating tissues that are typically not i r r a d i a t e d with s t a n d a r d techniques is not known. F u r t h e r m o r e , breast cancer patients generally experience long survival time and can therefore be at risk for development of late complications. Thus, an I M R T plan that irradiates tissues not typically included in t a n g e n t fields is less desirable from this perspective. At the same time, I M R T techniques have the potential to improve target homogeneity and spare specified n o r m a l tissues. Despite the use of computer-assisted optimization, d e t e r m i n a t i o n of the optimal plan for each patient is still based on clinical j u d g m e n t not only for costfunction specification but also for weighing the risks of irradiating the unknown against the benefits of delivering homogeneous t r e a t m e n t and reducing exposure to known vital structures.
Future Directions I M R T and inverse p l a n n i n g m a y r e s u l t in an o p t i m a l p l a n t h a t satisfies all clinical c r i t e r i a . However, t h e s e p o t e n t i a l gains will only be realized with a c c u r a t e delivery of the o p t i m i z e d plan. U n f o r t u n a t e l y , o p t i m i z a t i o n is c u r r e n t l y per-
f o r m e d on static C T scans c a p t u r e d at one point in time, yet the chest wall is a c o n s t a n t l y moving t a r g e t d u r i n g r a d i a t i o n delivery. I n c o r p o r a t i o n of chest wall m o t i o n into o p t i m i z a t i o n algor i t h m s 39,4~ and s u s p e n s i o n o f the b r e a t h i n g cycle d u r i n g I M R T delivery4~ a r e c u r r e n t topics of investigation. U n t i l (1) s e t u p accuracy a n d o r g a n m o t i o n issues are r o b u s t l y h a n d l e d , (2) t a r g e t volumes are m o r e carefully defined, and (3) bett e r clinical trade-offs and clinical d a t a a r e inc l u d e d in the d e r i v a t i o n o f the inverse p l a n n i n g cost function, the use of I M R T for t r e a t m e n t of the b r e a s t / c h e s t wall a n d r e g i o n a l nodes should be l i m i t e d to carefully d e s i g n e d clinical trials.
Acknowledgments W e would like to t h a n k Robin M a r s h a n d J e f f r e y R a d a w s k i for t h e i r assistance in the p r e p a r a t i o n of this m a n u s c r i p t .
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I M R T Treatment of Breast Cancer
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