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Accelerated Intensity-Modulated Radiotherapy to Breast in Prone Position: Dosimetric Results
Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 4, pp. 1251–1259, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2007.04.018
PHYSICS CONTRIBUTION
ACCELERATED INTENSITY-MODULATED RADIOTHERAPY TO BREAST IN PRONE POSITION: DOSIMETRIC RESULTS J. KEITH DEWYNGAERT, PH.D., GABOR JOZSEF, PH.D., JAMES MITCHELL, M.D., BARRY ROSENSTEIN, PH.D., AND SILVIA C. FORMENTI, M.D. Department of Radiation Oncology, New York University School of Medicine, New York, NY Purpose: To report the physics and dosimetry results of a trial of accelerated intensity-modulated radiotherapy to the whole breast with a concomitant boost to the tumor bed in patients treated in the prone position. Methods and Materials: Patients underwent computed tomography planning and treatment in the prone position on a dedicated treatment platform. The platform has an open aperture on the side to allow for the index breast to fall away from the chest wall. Noncontrast computed tomography images were acquired at 2.5- or 3.75-mm-thick intervals, from the level of the mandible to below the diaphragm. A dose of 40.5 Gy was delivered to the entire breast at 2.7-Gy fractions in 15 fractions. An additional dose of 0.5 Gy was delivered as a concomitant boost to the lumpectomy site, with a 1-cm margin, using inverse planning, for a total dose of 48 Gy in 15 fractions. No more than 10% of the heart and lung volume was allowed to receive >18 and >20 Gy, respectively. Results: Between September 2003 and August 2005, 91 patients were enrolled in the study. The median volume of heart that received $18 Gy was 0.5%, with a maximal value of 4.7%. The median volume of ipsilateral lung that received $20 Gy was 0.8%, with a maximum of 7.2%. Conclusion: This technique for whole breast radiotherapy is feasible and enables an accelerated regimen in the prone position while sparing the lung and heart. Ó 2007 Elsevier Inc. Prone breast irradiation, Intensity-modulated radiotherapy, IMRT, Accelerated regimen, Simultaneous integrated boost, SIB.
Several investigators have reported on the advantages of intensity-modulated radiotherapy (IMRT) planning for breast-conserving RT. The ability to modulate the beam intensity beyond that of a simple wedge has shown potential for reducing the lung, heart, and contralateral breast doses compared with conventional techniques. To date, no single approach to IMRT has been adopted as the standard. One common approach is the use of segmental IMRT, designed to track the isodose levels as seen in a beams’ eye view. This method has been shown to produce a more uniform dose distribution (1–4). Others have used a version of an electronic compensator to maintain a balance between the beamlets of the two tangential fields (5, 6). Both methods offer improved dose uniformity compared with conventional static fields and, as such, have been associated with reduced skin toxicities (7). Mixing non-IMRT beams with inverse-
planned IMRT tangent fields has been shown to produce more homogeneous distributions (8–10), and, compared with inverse-planned IMRT alone, it provides a simpler and more efficient format for planning (9). Transferring these techniques to patient setup in the prone position has received relatively little attention. Prone positioning originated as a method of treating women with pendulous breasts to reduce the acute morbidity (11–13). It has the additional advantage of reducing the volume of ‘‘in-field’’ normal tissue (12, 14–17). Goodman et al. (15) and Parhar et al. (18) reported using a simplified IMRT approach for prone positioning with the primary benefit of improving dose uniformity and normal tissue sparing, because the lung and heart tend to be spared better using the prone approach. Accelerated whole breast RT was successfully delivered in an important Canadian trial (19) that used fixed tangent fields without a boost. Subsequent to the publication of this work,
Reprint requests: J. Keith DeWyngaert, Ph.D., Department of Radiation Oncology, New York University School of Medicine, 160 E. 34th St., New York, NY 10016. Tel: (212) 731-5038; Fax: (212) 731-5013. E-mail: [email protected] Supported by Department of Defense DAMD 17-01-1-0345 and NYU Cancer Institute Core Grant.
Presented as a poster at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October 3–7, 2004, Atlanta, GA. Conflict of interest: none. Received Jan 11, 2007, and in revised form March 30, 2007. Accepted for publication April 4, 2007.
INTRODUCTION
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evidence has emerged that a dose–response effect may govern the risk of recurrence at the tumor bed, an indication for an additional boost dose to this area (20, 21). Several investigators have considered integrating the boost dose into the daily treatment regimen (8, 22, 23). This would result in an accelerated fractionation regimen to the lumpectomy site with a shortened length of the RT course, while allowing the plan to inherently account for the whole breast’s and the boost fields’ dose distribution together. The present study combined the advantages of prone positioning (increased heart and lung sparing) with an accelerated treatment regimen directed at both the whole breast and the tumor bed. The trial was designed to treat the whole breast to a dose of 40.5 Gy in 15 fractions, as determined by biologically equivalent dose (BED) calculations and supported by the results of the Canadian trial, which showed at 5 years equivalent efficacy and morbidity to that of a standard fractionation regimen. In addition, we tested the feasibility of adding a boost dose of 0.5 Gy/fraction to the lumpectomy site, to bring the dose to the tumor bed site to 48 Gy in 15 fractions. Two different planning strategies were used in this trial. An IMRT-generated simultaneous integrated boost (SIB) was used for the first consecutive 84 patients. That is, inverse
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planning was used to purposely generate regions of different doses within the breast. This approach was replaced with a concomitant IMRT boost added to supplement the nonIMRT tangent fields in the last 7 patients accrued. Specifically, inverse-planned IMRT boost fields were generated using the whole breast tangent fields as a base plan. In this way, the boost field beamlets were used to take into account the dose delivered through the tangents, as well as the interaction of the two fields with each other. The use of a hybrid approach to whole breast IMRT was originally reported by others (8–10). The same daily dose fractionation schema was used for both SIB and concomitant IMRT boost approaches. METHODS AND MATERIALS Patient data Stage I and II patients, who had biopsy-proven invasive breast cancer that had been excised with negative margins of $1 mm by breast-conserving surgery and had undergone either sentinel node biopsy or axillary node dissection, were eligible for this institutional review board–approved study. Excluded from the trial were patients with more than three involved lymph nodes identified in the axilla, requiring adjuvant axillary RT. Also excluded were carriers of connective tissue disorders. A total of 91 patients were enrolled in this
Fig. 1. Orthogonal views of accelerated intensity-modulated radiotherapy plan with only one field, an anterior oblique field, shown to indicate posterior border of tangent fields. Tumor bed, tumor bed plus 1-cm expansion, and isodose lines shown overlaid on computed tomography images. The 40.5-Gy isodose line (green) includes entire breast volume, and 48Gy isodose line (yellow), representing total dose to boost volume, encompasses planning target volume 2. Three fiducial markers seen: two representing medial and lateral field borders and one representing tattoo placed on patient to establish isocenter on daily basis. Isocenter shown as yellow circle positioned along beam central axis (dashed line) and horizontal to breast fiducial.
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study. Of the 91 patients, 51 had left-sided and 40 right-sided breast cancer. This study has reached accrual.
Computed tomography simulation The patients were placed in the prone position on a dedicated treatment platform for computed tomography (CT) planning and treatment. The platform, placed on top of the CT couch, contained an open aperture on one side to allow for the index breast to fall away from the chest wall. Noncontrast CT images were acquired at 2.5–3.75-mm-thick intervals, from the level of the mandible to below the diaphragm. Before the patients lay down prone on the platform for CT scanning, they lay supine and a radiation oncologist placed fiducial markers on their skin to clinically define the medial, lateral, caudal, and cephalad breast field borders.
Definition of planning target volumes The treatment volume was defined using the fiducial markers placed on the skin at CT simulation to delineate the field borders. The breast tissue was contoured using the CT images and edited as necessary to maintain a minimal distance of 5 mm inside these borders, including the posterior border, and 5 mm from the skin surface (24). This volume was labeled planning target volume 1 (PTV1) and represented the ipsilateral whole breast. The fields can be easily manipulated in the virtual simulation workspace to match the skin fiducial markers (Fig. 1). However, because the breast tissue pulls away from the chest wall, the fiducials move accordingly. The latissimus dorsi muscle can also be used as an anatomic landmark for the lateral extent of the breast tissue. If the fiducial falls anterior to the muscle, the posterior field border can be positioned further back (posterior to the skin fiducial) to maintain coverage of the underlying breast tissue that may be anchored anatomically to the muscle. A surrogate for the tumor bed was the postlumpectomy seroma region detectable on CT planning. The tumor bed was contoured and expanded uniformly by a 1-cm margin. This expanded volume
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became the boost target, PTV2, subject to the same physical constraints as PTV1. That is, PTV2 was 5 mm from the skin surface and $5 mm from the posterior, superior, and inferior borders as defined by the skin fiducials. The breast tissue (PTV1) that did not overlap with PTV2 was labeled the ipsilateral residual breast volume (IRBV) and was defined as the difference between the two volumes (PTV1 PTV2). In all patients, the ipsilateral lung and heart were contoured over the full range of images obtained.
Treatment planning The prescription dose to the whole breast was 40.5 Gy, with the boost region (PTV2) prescribed to receive 48 Gy in 15 fractions. The intent was to deliver 95% of the prescribed dose to 95% of the volumes. This was 38.5 Gy to cover 95% of the IRBV and 45.6 Gy to include 95% of PTV2. X-ray beam energies of 4, 6, and 10 MV were used. Two different planning strategies were used to supplement the dose to the boost region, both incorporating inverse-planned IMRT. For the purposes of this report, we made a distinction between a SIB (25), which incorporated the boost dose directly into a single plan (84 of 91 patients), and a concomitant IMRT boost, which added separate IMRT fields specifically designed to deliver the boost dose to the lumpectomy site on top of the ipsilateral whole breast dose (7 of 91 patients). The initial SIB approach used two to four IMRT fields. When more than two fields were chosen, a noncoplanar beam arrangement was used, most typically using three fields, inclusive of a medial field without couch rotation, combined with two lateral fields, each accompanied by a 10–20 couch rotation (Fig. 2). The boost was integrated directly into the IMRT optimization and treatment. For a medially located tumor bed, the beam arrangement can be flipped from that depicted in Fig. 2. Normal tissue constraints were designed so that no more than 10% of the heart and lung volume was allowed to receive >18 and >20 Gy, respectively. A 2-cm skin flash was added to the IMRT fields in conformance with the institution’s practice of
Fig. 2. Example of beam distribution for three-field intensity-modulated radiotherapy plan with simultaneous integrated boost. Single right anterior oblique medial beam with no couch angle and two left posterior oblique lateral beams, each with 15 couch rotation. Intersection of beams with skin surface shown.
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providing skin flash for standard breast tangent fields to account for daily positioning uncertainties. One disadvantage of relying solely on IMRT planning to achieve the intended dose distribution was the generation of dose distributions that often required IMRT field fluence editing to eliminate high-dose areas. In addition, the use of multiple, large, tangentlike IMRT fields with couch rotations extended the volume of nonbreast tissue included in the treatment fields superiorly and inferiorly. For these reasons, the technique evolved to a concomitant boost approach in the last 7 patients. Standard non-IMRT tangent fields were used to deliver the dose to the whole breast, supplemented daily by noncoplanar IMRT boost fields. The boost fields were required to enter and exit the breast within the volume of tissue included by the tangent fields, preventing the inclusion of additional nonbreast tissue within the irradiated volume. The tangential plans were created using two or three fields, with enhanced dynamic wedges as necessary. These plans were then submitted as a base plan for optimization of the boost fields. The optimization and calculations were performed using Helios/Eclipse software (Varian Medical Systems, Palo Alto, CA). Helios uses a gradient-dependent optimization algorithm to satisfy a given set of dose–volume objectives. In this instance, the constraints and priorities were established for PTV1, PTV2, body, lung, and heart. These values can be dynamically adjusted during optimization to improve the dose distribution beyond the expectations associated with the general set of constraints.
Dose fractionation and radiobiologic rationale for dose selection The linear-quadratic model (26) was used to determine whether the proposed accelerated intensity-modulated RT protocol yields a roughly equal probability of tumor control compared with a standard schedule, without increasing the potential for normal tissue damage. BEDs for the standard and accelerated IMRT schedules were calculated, as previously described (27). These calculations assume full repair takes place during the $24-h interval between fractions. Table 1 lists the BEDs for tumor control, early responses to radiation effects (erythema and desquamation), and late responses
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(telangiectasia and fibrosis). The choices for the a/b values used for these computations have been justified in previous studies (28–33). In addition, the hypofractionated treatment also represents an accelerated protocol in which the total dose is delivered in only 18 days. Therefore, little or no tumor proliferation is likely to occur during the course of this proposed treatment compared with during the standard treatment in which it is probable that tumor proliferation will take place, decreasing the chance of tumor control (34–37). As presented in Table 1, the inclusion of a cell proliferation correction factor produces small decreases in the BEDs for the standard treatment. Therefore, taking into consideration tumor proliferation during treatment, the accelerated IMRT schedule results in BED values greater than, or equal to, the standard treatment for a/b values of either 2 or 4 Gy and only slightly lower values using a 10-Gy a/b value.
RESULTS Table 2 lists the dosimetric results of this study for the IRBV for which 100% of the prescribed dose was 40.5 Gy. The data are reported as the percentage of volume that received 95% of 40.5 Gy or 100%, 110%, 120%, and 125% of 40.5 Gy. In this way, the dose coverage and hot spots are both evident. The dose coverage for PTV2 is summarized in Table 3, with the volume data for PTV1 and PTV2. The data are reported as the dose covering 95% and 90% of PTV2. The prescription dose for PTV2 was 48 Gy. The PTV2/PTV1 ratio, the percentage of the breast occupied by the tumor bed PTV, was 4–55%, with 10 of 91 patients demonstrating a PTV2 volume >25% of the whole breast volume. The mean volume of whole breast (PTV1) that received a minimum of 48 Gy (V48) was 27.2%. Ideally, PTV2 and V48 would coincide. A gauge of the conformality of the population of plans is a measure of how well the fractional volume of breast receiving >48 Gy mimicked the relative volume statistics. An index of conformality was defined as the volume enclosed by the prescription isodose surface to
Table 1. Biologically equivalent doses for AIMRT schedule as function of a/b ratios Normal tissue response Fibrosis Telangiectasia Erythema Desquamation
Tumor control Tumor Tumor* Tumor Tumor* Tumor Tumor*
a/b (Gy)
Standard schedule (2 Gy 23 fractions in 39 d)
AIMRT schedule (2.7 Gy 15 in 18 d)
2 4 8 11
92 Gy2 69 Gy4 58 Gy8 54 Gy11
95 Gy2 68 Gy4 54 Gy8 50 Gy11
a/b (Gy)
Standard schedule (2 Gy 30 fractions in 39 d)
AIMRT schedule (3.2 Gy 15 fractions in 18 d)
2 2 4 4 10 10
120 Gy2 116 Gy2 90 Gy4 86 Gy4 72 Gy10 68 Gy10
125 Gy2 125 Gy2 86 Gy4 86 Gy4 63 Gy10 63 Gy10
Abbreviation: AIMRT = accelerated intensity-modulated radiotherapy. * Taking into account cell proliferation during treatment course.
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Table 2. Dosimetric summary for ipsilateral residual breast volume for 91 patients treated with prone AIMRT IRBV receiving indicated percentage of prescription dose (40.5 Gy) (%) Median SD Mean Minimum Maximum
V95 (38.5 Gy)
V100 (40.5 Gy)
V110 (44.6 Gy)
V120 (48.6 Gy)
V125 (50.6 Gy)
98.3 2.5 97.6 87.8 100.0
94.8 4.9 93.6 74.4 100.0
33.4 15.2 36.0 4.3 92.8
13.2 9.0 14.1 0.8 48.5
1.2 3.3 2.6 0 13.3
Abbreviations: AIMRT = accelerated intensity-modulated radiotherapy; IRBV = ipsilateral residual breast volume (IRBV = PTV1 PTV2); V95, V100, V110, V120, V125 = % volume of whole breast receiving minimum of 95%, 100%, 110%, 120%, and 125%, of prescription dose, respectively; SD = standard deviation; PTV1 = breast tissue; PTV2 = tumor bed + 1-cm expansion.
the target volume: PITV = V48 Gy/VPTV2, where V48 Gy is the volume enclosed by the 48-Gy isodose surface and VPTV2 is the volume of the boost structure, PTV2. The mean ratio of the 48-Gy volume to the PTV2 was 1.9 (median, 1.8; range, 0.9–4.2). The median volume coverage of PTV2 with 48 Gy was 97.2% (range, 78–100%). The median dose that covered 95% of PTV2 was 48.2 Gy (range, 44.6–49.5). A 95% dose coverage to 95% of the PTV2 was achieved in 88 of 91 cases. The overall plan dose maximum had a median value of 128.9%. The PTV2 prescribed dose of 48 Gy was 118.5% greater than the whole breast prescribed dose of 40.5 Gy. As such, the 128.9% dose maximum (52.2 Gy) represented an increase of approximately 10% more than the PTV2 prescription dose of 48 Gy. In Table 4, the data are organized according to three planning strategies. Of the 91 patients, 21 were treated using three or four noncoplanar SIB fields, 63 were treated with two SIB fields, and 7 were treated with the concomitant boost approach. For all three categories, the median dose that covered 95% of PTV2 was >48 Gy and the median index of conformality, PITV, was #2. Although the concomitant boost approach had the greatest median PITV, it offered the best PTV2 coverage, with the smallest high-dose region and dose maximum. The overlap between the results of the three techniques is sufficient to support dosimetric equivalence. The heart and lung doses are summarized in Table 5. The minimal dose covering 5% of the organ (D5) and the volume that received >18 Gy for the heart and >20 Gy for the ipsilateral lung are reported. The maximal volume that received 18 Gy to the
heart and 20 Gy to the lung was 4.7% and 7.2%, respectively, observing the 10% limit required by the protocol. The median volume of the heart that received a minimum of 18 Gy was reported for left-sided breast cancers only and was 0.5%. No measurable volume of the heart received >18 Gy for right-sided breast cancers. The median D5 for the heart for all 91 patients was 2.0 Gy, with a maximum of 10.5 Gy. The median volume of the ipsilateral lung that received $20 Gy was 0.8%. The median D5 for the ipsilateral lung was 3.0 Gy, with a maximum of 29.6 Gy. In 4 of the 91 accrued patients, 5% of the ipsilateral lung volume received >20 Gy; however, as stated previously, no instances occurred in which >10% of the lung volume exceeded the protocol limit of 20 Gy. The median values for the IRBV, PTV2, heart volume, and lung volume are displayed in a dose–volume histogram style plot (Fig. 3). The values were connected by a drawn dotted line to help depict the shape of the dose–volume histograms and facilitate the interpretation of the relative relationships of the tabulated values. The global dose maximum is also included and used as the upper dose limit for the dose– volume histogram plot of PTV2. The volume of residual breast that received 120% of the prescription dose was chosen as a measure of how much of the boost dose ‘‘leaked’’ into the surrounding breast tissue. The total dose to the boost site was 48 Gy (118.5% of the prescription dose). Therefore, it was not surprising to detect a margin of high dose surrounding the PTV2. Figure 4 illustrates the correlation of the volume of the whole breast occupied by PTV2 to the volume of high-dose regions in the
Table 3. PTV2 dose coverage and volume summary for 91 patients treated with prone AIMRT PTV2
Median SD Mean Minimum Maximum
PTV1 (cm3)
PTV2 (cm3)
PTV2/PTV1 (fractional volume)
D95 (Gy)
D90 (Gy)
641.6 540.0 765.7 120.6 2743.8
81.6 94.5 111.7 21.2 604.5
0.14 0.09 0.16 0.04 0.55
48.24 0.83 48.12 44.63 49.46
48.64 0.64 48.56 46.37 49.90
Abbreviations: D95 and D90 = minimal dose covering 95% and 90% of organ, respectively; other abbreviations as in Table 2.
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Table 4. Variation of dosimetric parameters as function of treatment technique 3–4-Field SIB
2-Field SIB
Concomitant boost
Patients (n) PTV2 D95 (Gy) PITV IRBV, 40.5 Gy (%) IRBV, 48 Gy (%) Dose maximum (Gy)
21 48.13 (0.93) 1.52 (0.67) 92.0 (5.7) 7.4 (7.0) 53.52 (1.3)
63 48.32 (0.82) 1.81 (0.57) 95.3 (4.7) 14.3 (9.1) 52.02 (1.12)
7 48.48 (0.35) 2.01 (0.56) 94.5 (2.8) 6.2 (7.6) 50.83 (0.64)
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Volume (%)
Parameter
A number of investigators have discussed the advantages of IMRT for breast homogeneity and of the rationale for integrating the boost into the daily treatment sessions (8, 22, 23). A hybrid approach was suggested to make the process more efficient and eliminate certain inhomogeneities that can arise in inverse-planned opposed tangents (8–10). With dose gradients of 119% intentionally inserted into regions of the breast (48 Gy/40.5 Gy), the risk of dose-related
Table 5. Dosimetric results for heart and ipsilateral lung Ipsilateral lung
Median SD Mean Minimum Maximum
Heart*
0
0
10
20
30
40
50
60
Dose (Gy)
Fig. 3. Median dose–volume histogram values plotted. Solid triangles represent dose–volume histogram for residual breast (planning target volume 1 [breast tissue] planning target volume 2 [tumor bed plus 1-cm expansion]); open triangles, planning target volume 2 values; solid diamonds, heart values; and open diamonds, lung values. Median dose maximum of 52.2 Gy also included. Lines included only to aid in individual dose–volume histogram values.
complications becomes a central consideration during planning. The three-field SIB technique initially adopted showed overall hot spots of 130%. As seen in Table 1, such a hot spot could be quite relevant when larger fractions are used, with greater BEDs for fibrosis associated with an accelerated regimen. Recent studies have suggested a relationship between the development of Grade 3 fibrosis and certain ATM gene sequences (38, 39). It is possible that carriers of specific genetic profiles could be particularly susceptible to the risk of complications. To investigate this association
80 70
% Volume (V48)
DISCUSSION
40
20
Abbreviations: SIB = simultaneous integrated boost; PITV = index of conformality (V48/VPTV2); V48 = volume of whole breast receiving minimum of 48 Gy; other abbreviations as in Table 2. Data presented as median with SD in parentheses.
whole breast and residual breast. Although a relationship between this ratio and the whole breast volume receiving a minimum of 48 Gy was apparent, no clear relationship was detectable with the IRBV once the PTV2 was excluded. The dose to the ipsilateral lung was also considered separately for right- and left-sided lesions (Fig. 5). The D5 values for each case are presented and grouped by right or left side. The two groups appeared similar, suggesting that the lung doses were only minimally decreased in left-sided breast cancers, as a result of the sparing dictated by the proximity of the heart in these patients. The median value was 2.6 Gy for the left breast cases and 3.5 Gy for the right breast cases.
60
60 50 40 30 20 10
D5 (Gy)
V20 Gy (%)
D5 (Gy)
V18 Gy (%)
3.0 5.3 4.5 0 29.6
0.8 1.6 1.3 0 7.2
2.0 2.2 2.7 0 10.5
0.5 1.3 1.0 0 4.7
Abbreviations: D5 = minimal dose covering 5% of organ; V20 Gy and V18 Gy = volume that received >20 Gy (lung) and >18 Gy (heart), respectively; SD = standard deviation. Values expressed as dose for D5 and percentage of volume for V18 Gy and V20 Gy. * Women with left-sided breast cancers only included in analysis for V18 Gy to heart.
0 0.00
0.10
0.20
0.30
0.40
0.50
0.60
Ratio of PTV2 to PTV1
Fig. 4. Volume of the entire breast receiving a dose >48 Gy (V48) presented as function of fractional volume of breast occupied by tumor bed plus 1-cm expansion (planning target volume 2 [PTV2]; solid triangles). Because a greater fraction of breast becomes occupied by boost volume (PTV2), a greater percentage of breast received $48 Gy, as expected. Similar data shown for residual breast (open triangles). Percentage of residual breast volume receiving a minimum of 48 Gy did not increase as the fractional volume occupied by PTV2 increased. Median percentage volume receiving $48 Gy was 13.2% for the residual breast volume and 27.2% for the whole breast (PTV1).
D5: Dose at 5% Volume Level for DVH of Ipsilateral Lung (Gy)
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0
10 20 30 40 50 Case Number for Right Breast and Left Breast
60
Fig. 5. Lung doses encompassing 5% of ipsilateral lung (D5) with accelerated intensity-modulated radiotherapy to the breast. Data segregated into left-sided lesions (closed triangles) and right-sided lesions (open triangles).
further, this study included a collection of blood samples for polymorphism studies of candidate genes. Because the concomitant boost approach tended to be associated with the lowest dose maximum and the smallest volumes of high dose, we eventually migrated to this approach. This choice was supported by the relative ease of planning a concomitant boost plan compared with planning the SIB plans. Generally, the conformality index should be a measure not just of how well the isodose conforms to its target, but also of the high-dose volume of nontarget tissue that surrounds the target. Considering the data once all three planning approaches were combined, the median index of conformality for PTV2 was 1.80. When analyzed separately, they ranged from 1.52 to 2.01 (Table 4). Values >1.0 indicate dose volumes larger than the target volume. From the radiosurgery data, values between 1 and 2 are considered acceptable (40). Although the concomitant boost approach has the greatest conformality index (extra volume of high dose), it has the lowest fractional IRBV receiving the high dose. With the limitation of the small number of patients receiving the concomitant boost technique, the median fractional volume of the breast occupied by the PTV2 was 64% compared with the SIB techniques. This reflects a smaller median PTV2. Small increases in the conformality index for the concomitant boost technique compared with the other techniques would represent a much smaller absolute IRBV. Three cases had a conformality index >3.0. For each case, the target occupied a large cross-sectional area in the beams’ eye view, with a narrow lateral extent. In these instances, it is difficult to maintain a low conformality index because of the table rotation limitations with the patient lying prone. Data have suggested that cardiac toxicity can be associated with the volume of heart in the field and that increased mortality from lung cancer deaths can be similarly associated with the dose received by the lung (41–45). With prone positioning, the breast tissue falls away from the chest wall. Typically, the heart and lung could be excluded from the treatment fields, thus maintaining doses to the lung and heart
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well below our target values. An important argument often used in support of partial breast irradiation is lung and heart sparing. The Radiation Therapy Oncology Group partial breast protocol 0413 limited <15% of the ipsilateral lung to receive >30% of the prescribed dose (11.5 Gy) and <5% of the heart volume to receive >40% of the prescribed dose (15.4 Gy) for left-sided lesions (46). For right-sided lesions, the heart constraint decreases to <5% of the volume to receive >5% of the prescribed dose (1.9 Gy). The protocol calls for 38.5 Gy to be delivered in 10 fractions within 5 days. The data presented here were not parsed at the 15% volume level for the ipsilateral lung doses nor planned for the partial breast; however, 90% of our cases were able to meet the 11.5-Gy dose constraint (Fig. 5) at the more stringent 5% volume level, while treating the whole breast and delivering a boost to the tumor cavity. For the left-sided lesions, all the plans met the 15.4-Gy dose constraint for the heart, with a median value of 2.0 Gy (range, 0–10.5 Gy). For the right-sided lesions, the median value for 5% of the heart was 1.5 Gy, with >92% (37 of 40) of the cases meeting the Radiation Therapy Oncology Group 1.9-Gy constraint. Figure 5 also demonstrates similar results for lung dosimetry, independent of laterality. The low doses associated with scattered radiation from combined chemoradiotherapy to the breast have been linked to an increased risk of leukemia (47, 48). Woo et al. (49) considered the factors that lead to an increase in scatter dose to different parts of the body. The most significant factor was the use of physical wedges. An inverse relationship with cup size was established for doses to the contralateral breast. No physical wedges were used in this study and, at New York University hospitals, have not been used for >10 years. The dose to the contralateral breast due to scatter from the treated breast remains to be studied for women in the prone position. Supplementing the dose to the tumor bed, either as an integrated IMRT boost or as a separate concomitant boost, is dependent on the ability to properly target the tumor bed. The strategy of integrating the boost dose into the daily fractionation also requires that the target location and size maintain stability during the RT course. For the present work, the seroma seen on CT was considered a surrogate for the tumor bed. Oh et al. (50) examined the change in the excision cavity after a RT course by comparing a CT scan at the end of treatment with that obtained at simulation. Although they observed minimal changes in the whole breast volume, they observed a dramatic reduction in the size of the cavity during the treatment course (22% mean reduction). It is likely that modification of the cavity on the basis of the volume visualized at simulation results in overestimation of the volume assigned to PTV2. In addition, the accuracy of targeting is hampered by interand intrafraction changes. Recent evidence has suggested that the respiratory-associated movement of the breast is only 1–2 mm during treatment for patients in the prone position (51, 52). We are currently studying the interfraction changes that occur in the prone position through an application of cone-beam CT.
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Finally, none of the patients in this trial also underwent treatment simulation in the supine position, making it impossible to compare the effect of the setup on the IMRT results. The preliminary results of a study by Parhar et al. (18) that compares the effect of positioning, prone versus supine, on the dose to the lung and heart suggest that the prone setup achieves better normal tissue sparing for most patients. CONCLUSION The results of the present study have shown that an accelerated RT regimen to the whole breast with an integrated boost in the prone position is feasible. Positioning the
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patients prone enables sparing of the lung and heart, generally to less than levels considered acceptable for partial breast RT (46). The addition of separate and smaller IMRT boost fields integrated with non-IMRT tangent fields was a more efficient planning method and appeared to offer greater control of the high-dose regions compared with an IMRT-SIB approach. A remaining question is the stability of the high-dose target within the breast. Data have suggested that the seroma decreases in size during RT (50) and that the movement due to respiratory motion is minimal (51, 52). Our on-going study of interfraction setup uncertainties should answer our ability to target high-dose regions to specific regions within the breast.
REFERENCES 1. Evans PM, Donovan EM, Partridge M, et al. The delivery of intensity modulated radiotherapy to the breast using multiple static fields. Radiother Oncol 2000;57:79–89. 2. Kestin LL, Sharpe MB, Frazier RC, et al. Intensity modulation to improve dose uniformity with tangential breast radiotherapy: Initial clinical experience. Int J Radiat Oncol Biol Phys 2000; 48:1559–1568. 3. Lo YC, Yasuda G, Fitzgerald TJ, et al. Intensity modulation for breast treatment using static multi-leaf collimators. Int J Radiat Oncol Biol Phys 2000;46:187–194. 4. Vicini FA, Sharpe M, Kestin L, et al. Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2002;54:1336–1344. 5. Chui CS, Hong L, Hunt M, et al. A simplified intensity modulated radiation therapy technique for the breast. Med Phys 2002; 29:522–529. 6. Li JS, Freedman GM, Price R, et al. Clinical implementation of intensity-modulated tangential beam irradiation for breast cancer. Med Phys 2004;31:1023–1031. 7. Freedman GM, Anderson PR, Li JS, et al. Intensity modulated radiation therapy (IMRT) decreases acute skin toxicity for women receiving radiation for breast cancer. Am J Clin Oncol Cancer Clin Trials 2006;29:66–70. 8. Hurkmans CW, Meijer GJ, van Vliet-Vroegindeweij C, et al. High-dose simultaneously integrated breast boost using intensity-modulated radiotherapy and inverse optimization. Int J Radiat Oncol Biol Phys 2006;66:923–930. 9. Mayo CS, Urie MM, Fitzgerald TJ. Hybrid IMRT plans—Concurrently treating conventional and IMRT beams for improved breast irradiation and reduced planning time. Int J Radiat Oncol Biol Phys 2005;61:922–932. 10. van Asselen B, Raaijmakers CPJ, Hofman P, et al. An improved breast irradiation technique using three-dimensional geometrical information and intensity modulation. Radiother Oncol 2001;58:341–347. 11. Algan O, Fowble B, McNeeley S, et al. Use of the prone position in radiation treatment for women with early stage breast cancer. Int J Radiat Oncol Biol Phys 1998;40:1137–1140. 12. Mahe MA, Classe JM, Dravet F, et al. Preliminary results for prone-position breast irradiation. Int J Radiat Oncol Biol Phys 2002;52:156–160. 13. Merchant TE, Mccormick B. Prone position breast irradiation. Int J Radiat Oncol Biol Phys 1994;30:197–203. 14. Formenti SC, Truong MT, Goldberg JD, et al. Prone accelerated partial breast irradiation after breast-conserving surgery: Preliminary clinical results and dose–volume histogram analysis. Int J Radiat Oncol Biol Phys 2004;60:493–504.
15. Goodman KA, Hong L, Wagman R, et al. Dosimetric analysis of a simplified intensity modulation technique for prone breast radiotherapy. Int J Radiat Oncol Biol Phys 2004;60:95–102. 16. Griem KL, Fetherston P, Kuznetsova M, et al. Three-dimensional photon dosimetry: A comparison of treatment of the intact breast in the supine and prone position. Int J Radiat Oncol Biol Phys 2003;57:891–899. 17. Kurtman C, Andrieu MN, Hicsonmez A, et al. Three-dimensional conformal breast irradiation in the prone position. Braz J Med Biol Res 2003;36:1441–1446. 18. Parhar PK, Constantine C, Racsa-Alamgir M, et al. 1082: Preliminary results of NYU 05-181, a prospective trial to establish the individual optimal positioning for breast radiotherapy [Abstract]. Int J Radiat Oncol Biol Phys 2006;66(Suppl.):S177. 19. Whelan T, MacKenzie R, Julian J, et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 2002; 94:1143–1150. 20. Bartelink H, Horiot J, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345: 1378–1387. 21. Poortmans P, Bartelink H, Horiot JC, et al. The influence of the boost technique on local control in breast conserving treatment in the EORTC ‘‘boost versus no boost’’ randomised trial. Radiother Oncol 2004;72:25–33. 22. Guerrero M, Li XA, Earl MA, et al. Simultaneous integrated boost for breast cancer using IMRT: A radiobiological and treatment planning study. Int J Radiat Oncol Biol Phys 2004;59: 1513–1522. 23. Teh B, Lu H, Sobremonte S, et al. The potential use of intensity modulated radiotherapy (IMRT) in women with pectus excavatum desiring breast-conserving therapy. Breast J 2001;7: 233–239. 24. Hong L, Hunt M, Chui C, et al. Intensity-modulated tangential beam irradiation of the intact breast. Int J Radiat Oncol Biol Phys 1999;44:1155–1164. 25. Mohan R, Wu Q, Manning M, et al. Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers. Int J Radiat Oncol Biol Phys 2000;46:619–630. 26. Lea DE, Catcheside DG. The mechanism of the induction by radiation of chromosome aberrations in Tradescantia. J Genet 1942;44:216–245. 27. Rosenstein BS, Lymberis SC, Formenti SC. Biologic comparison of partial breast irradiation protocols. Int J Radiat Oncol Biol Phys 2004;60:1393–1404.
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28. Archambeau JO, Pezner R, Wasserman T. Pathophysiology of irradiated skin and breast. Int J Radiat Oncol Biol Phys 1995; 31:1171–1185. 29. Matthews JHL, Meeker BE, Chapman JD. Response of human tumor cell lines in vitro to fractionated irradiation. Int J Radiat Oncol Biol Phys 1989;16:133–138. 30. Steel GG, Deacon JM, Duchesne GM, et al. The dose-rate effect in human tumor cells. Radiother Oncol 1987;9:299–310. 31. Thames HD, Bentzen SM, Turesson I, et al. Time–dose factors in radiotherapy—A review of the human data. Radiother Oncol 1990;19:219–235. 32. Turesson I, Thames HD. Repair capacity and kinetics of human skin during fractionated radiotherapy—Erythema, desquamation, and telangiectasia after 3 and 5 years follow-up. Radiother Oncol 1989;15:169–188. 33. Yamada Y, Ackerman I, Franssen E, et al. Does the dose fractionation schedule influence local control of adjuvant radiotherapy for early stage breast cancer? Int J Radiat Oncol Biol Phys 1999;44:99–104. 34. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:679–694. 35. Haustermans K, Fowler J, Geboes K, et al. Relationship between potential doubling time (T-pot), labeling index and duration of DNA synthesis in 60 esophageal and 35 breast tumors: Is it worthwhile to measure T-pot? Radiother Oncol 1998;46: 157–167. 36. Stanton PD, Cooke TG, Forster G, et al. Cell kinetics in vivo of human breast cancer. Br J Surg 1996;83:98–102. 37. Travis EL, Tucker SL. Isoeffect models and fractionated radiation therapy. Int J Radiat Oncol Biol Phys 1987;13:283–287. 38. Andreassen CN, Overgaard J, Alsner J, et al. ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy. Int J Radiat Oncol Biol Phys 2006;64:776–783. 39. Ho AY, Atencio DP, Peters S, et al. Genetic predictors of adverse radiotherapy effects: The gene-pare project. Int J Radiat Oncol Biol Phys 2006;65:646–655. 40. Shaw E, Kline R, Gillin M, et al. Radiation Therapy Oncology Group radiosurgery quality assurance guidelines. Int J Radiat Oncol Biol Phys 1993;27:1231–1239. 41. Abe O, Abe R, Enomoto K, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;366:2087–2106.
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42. Darby SC, McGale P, Taylor CW, et al. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: Prospective cohort study of about 300 000 women in US SEER cancer registries. Lancet Oncol 2005;6: 557–565. 43. Marks LB, Yu XL, Prosnitz RG, et al. The incidence and functional consequences of RT-associated cardiac perfusion defects. Int J Radiat Oncol Biol Phys 2005;63:214–223. 44. Prosnitz RG, Marks LB. Radiation-induced heart disease: Vigilance is still required. J Clin Oncol 2005;23:7391–7394. 45. Seddon B, Cook A, Gothard L, et al. Detection of defects in myocardial perfusion imaging in patients with early breast cancer treated with radiotherapy. Radiother Oncol 2002;64:53–63. 46. Vicini F, White J, Arthur D, et al. NSABP Protocol B39/RTOG Protocol 0413: A randomized phase II study of conventional whole breast irradiation (WBI) versus partial breast irradiation for women with stage 0, I or II breast cancer. Available at: www.rtog.org 2004. Accessed January 11, 2007. Radiation Therapy Oncology Group; 2005. 47. Crump M, Tu DS, Shepherd L, et al. Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: A report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:3066–3071. 48. Smith RE, Bryant J, DeCillis A, et al. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 2003;21:1195–1204. 49. Woo TCS, Pignol JP, Rakovitch E, et al. Body radiation exposure in breast cancer radiotherapy: Impact of breast IMRT and virtual wedge compensation techniques. Int J Radiat Oncol Biol Phys 2006;65:52–58. 50. Oh KS, Kong FM, Griffith KA, et al. Planning the breast tumor bed boost: Changes in the excision cavity volume and surgical scar location after breast-conserving surgery and whole-breast irradiation. Int J Radiat Oncol Biol Phys 2006;66:680–686. 51. DeWyngaert JK, Mitchell JD, Alonso-Basanta M, et al. 1083: Intrafraction organ motion in breast radiation therapy: A comparison of prone versus supine patient positioning [Abstract]. Int J Radiat Oncol Biol Phys 2006;66:S177–S178. 52. Becker SJ, Patel RR, Mackie TR. 4DCT intrafraction motion margin assessment in breast cancer treatments [Abstract]. Radiother Oncol 2005;76(Suppl.):S74.
doi:10.1016/j.ijrobp.2007.04.018
PHYSICS CONTRIBUTION
ACCELERATED INTENSITY-MODULATED RADIOTHERAPY TO BREAST IN PRONE POSITION: DOSIMETRIC RESULTS J. KEITH DEWYNGAERT, PH.D., GABOR JOZSEF, PH.D., JAMES MITCHELL, M.D., BARRY ROSENSTEIN, PH.D., AND SILVIA C. FORMENTI, M.D. Department of Radiation Oncology, New York University School of Medicine, New York, NY Purpose: To report the physics and dosimetry results of a trial of accelerated intensity-modulated radiotherapy to the whole breast with a concomitant boost to the tumor bed in patients treated in the prone position. Methods and Materials: Patients underwent computed tomography planning and treatment in the prone position on a dedicated treatment platform. The platform has an open aperture on the side to allow for the index breast to fall away from the chest wall. Noncontrast computed tomography images were acquired at 2.5- or 3.75-mm-thick intervals, from the level of the mandible to below the diaphragm. A dose of 40.5 Gy was delivered to the entire breast at 2.7-Gy fractions in 15 fractions. An additional dose of 0.5 Gy was delivered as a concomitant boost to the lumpectomy site, with a 1-cm margin, using inverse planning, for a total dose of 48 Gy in 15 fractions. No more than 10% of the heart and lung volume was allowed to receive >18 and >20 Gy, respectively. Results: Between September 2003 and August 2005, 91 patients were enrolled in the study. The median volume of heart that received $18 Gy was 0.5%, with a maximal value of 4.7%. The median volume of ipsilateral lung that received $20 Gy was 0.8%, with a maximum of 7.2%. Conclusion: This technique for whole breast radiotherapy is feasible and enables an accelerated regimen in the prone position while sparing the lung and heart. Ó 2007 Elsevier Inc. Prone breast irradiation, Intensity-modulated radiotherapy, IMRT, Accelerated regimen, Simultaneous integrated boost, SIB.
Several investigators have reported on the advantages of intensity-modulated radiotherapy (IMRT) planning for breast-conserving RT. The ability to modulate the beam intensity beyond that of a simple wedge has shown potential for reducing the lung, heart, and contralateral breast doses compared with conventional techniques. To date, no single approach to IMRT has been adopted as the standard. One common approach is the use of segmental IMRT, designed to track the isodose levels as seen in a beams’ eye view. This method has been shown to produce a more uniform dose distribution (1–4). Others have used a version of an electronic compensator to maintain a balance between the beamlets of the two tangential fields (5, 6). Both methods offer improved dose uniformity compared with conventional static fields and, as such, have been associated with reduced skin toxicities (7). Mixing non-IMRT beams with inverse-
planned IMRT tangent fields has been shown to produce more homogeneous distributions (8–10), and, compared with inverse-planned IMRT alone, it provides a simpler and more efficient format for planning (9). Transferring these techniques to patient setup in the prone position has received relatively little attention. Prone positioning originated as a method of treating women with pendulous breasts to reduce the acute morbidity (11–13). It has the additional advantage of reducing the volume of ‘‘in-field’’ normal tissue (12, 14–17). Goodman et al. (15) and Parhar et al. (18) reported using a simplified IMRT approach for prone positioning with the primary benefit of improving dose uniformity and normal tissue sparing, because the lung and heart tend to be spared better using the prone approach. Accelerated whole breast RT was successfully delivered in an important Canadian trial (19) that used fixed tangent fields without a boost. Subsequent to the publication of this work,
Reprint requests: J. Keith DeWyngaert, Ph.D., Department of Radiation Oncology, New York University School of Medicine, 160 E. 34th St., New York, NY 10016. Tel: (212) 731-5038; Fax: (212) 731-5013. E-mail: [email protected] Supported by Department of Defense DAMD 17-01-1-0345 and NYU Cancer Institute Core Grant.
Presented as a poster at the 46th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), October 3–7, 2004, Atlanta, GA. Conflict of interest: none. Received Jan 11, 2007, and in revised form March 30, 2007. Accepted for publication April 4, 2007.
INTRODUCTION
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evidence has emerged that a dose–response effect may govern the risk of recurrence at the tumor bed, an indication for an additional boost dose to this area (20, 21). Several investigators have considered integrating the boost dose into the daily treatment regimen (8, 22, 23). This would result in an accelerated fractionation regimen to the lumpectomy site with a shortened length of the RT course, while allowing the plan to inherently account for the whole breast’s and the boost fields’ dose distribution together. The present study combined the advantages of prone positioning (increased heart and lung sparing) with an accelerated treatment regimen directed at both the whole breast and the tumor bed. The trial was designed to treat the whole breast to a dose of 40.5 Gy in 15 fractions, as determined by biologically equivalent dose (BED) calculations and supported by the results of the Canadian trial, which showed at 5 years equivalent efficacy and morbidity to that of a standard fractionation regimen. In addition, we tested the feasibility of adding a boost dose of 0.5 Gy/fraction to the lumpectomy site, to bring the dose to the tumor bed site to 48 Gy in 15 fractions. Two different planning strategies were used in this trial. An IMRT-generated simultaneous integrated boost (SIB) was used for the first consecutive 84 patients. That is, inverse
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planning was used to purposely generate regions of different doses within the breast. This approach was replaced with a concomitant IMRT boost added to supplement the nonIMRT tangent fields in the last 7 patients accrued. Specifically, inverse-planned IMRT boost fields were generated using the whole breast tangent fields as a base plan. In this way, the boost field beamlets were used to take into account the dose delivered through the tangents, as well as the interaction of the two fields with each other. The use of a hybrid approach to whole breast IMRT was originally reported by others (8–10). The same daily dose fractionation schema was used for both SIB and concomitant IMRT boost approaches. METHODS AND MATERIALS Patient data Stage I and II patients, who had biopsy-proven invasive breast cancer that had been excised with negative margins of $1 mm by breast-conserving surgery and had undergone either sentinel node biopsy or axillary node dissection, were eligible for this institutional review board–approved study. Excluded from the trial were patients with more than three involved lymph nodes identified in the axilla, requiring adjuvant axillary RT. Also excluded were carriers of connective tissue disorders. A total of 91 patients were enrolled in this
Fig. 1. Orthogonal views of accelerated intensity-modulated radiotherapy plan with only one field, an anterior oblique field, shown to indicate posterior border of tangent fields. Tumor bed, tumor bed plus 1-cm expansion, and isodose lines shown overlaid on computed tomography images. The 40.5-Gy isodose line (green) includes entire breast volume, and 48Gy isodose line (yellow), representing total dose to boost volume, encompasses planning target volume 2. Three fiducial markers seen: two representing medial and lateral field borders and one representing tattoo placed on patient to establish isocenter on daily basis. Isocenter shown as yellow circle positioned along beam central axis (dashed line) and horizontal to breast fiducial.
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study. Of the 91 patients, 51 had left-sided and 40 right-sided breast cancer. This study has reached accrual.
Computed tomography simulation The patients were placed in the prone position on a dedicated treatment platform for computed tomography (CT) planning and treatment. The platform, placed on top of the CT couch, contained an open aperture on one side to allow for the index breast to fall away from the chest wall. Noncontrast CT images were acquired at 2.5–3.75-mm-thick intervals, from the level of the mandible to below the diaphragm. Before the patients lay down prone on the platform for CT scanning, they lay supine and a radiation oncologist placed fiducial markers on their skin to clinically define the medial, lateral, caudal, and cephalad breast field borders.
Definition of planning target volumes The treatment volume was defined using the fiducial markers placed on the skin at CT simulation to delineate the field borders. The breast tissue was contoured using the CT images and edited as necessary to maintain a minimal distance of 5 mm inside these borders, including the posterior border, and 5 mm from the skin surface (24). This volume was labeled planning target volume 1 (PTV1) and represented the ipsilateral whole breast. The fields can be easily manipulated in the virtual simulation workspace to match the skin fiducial markers (Fig. 1). However, because the breast tissue pulls away from the chest wall, the fiducials move accordingly. The latissimus dorsi muscle can also be used as an anatomic landmark for the lateral extent of the breast tissue. If the fiducial falls anterior to the muscle, the posterior field border can be positioned further back (posterior to the skin fiducial) to maintain coverage of the underlying breast tissue that may be anchored anatomically to the muscle. A surrogate for the tumor bed was the postlumpectomy seroma region detectable on CT planning. The tumor bed was contoured and expanded uniformly by a 1-cm margin. This expanded volume
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became the boost target, PTV2, subject to the same physical constraints as PTV1. That is, PTV2 was 5 mm from the skin surface and $5 mm from the posterior, superior, and inferior borders as defined by the skin fiducials. The breast tissue (PTV1) that did not overlap with PTV2 was labeled the ipsilateral residual breast volume (IRBV) and was defined as the difference between the two volumes (PTV1 PTV2). In all patients, the ipsilateral lung and heart were contoured over the full range of images obtained.
Treatment planning The prescription dose to the whole breast was 40.5 Gy, with the boost region (PTV2) prescribed to receive 48 Gy in 15 fractions. The intent was to deliver 95% of the prescribed dose to 95% of the volumes. This was 38.5 Gy to cover 95% of the IRBV and 45.6 Gy to include 95% of PTV2. X-ray beam energies of 4, 6, and 10 MV were used. Two different planning strategies were used to supplement the dose to the boost region, both incorporating inverse-planned IMRT. For the purposes of this report, we made a distinction between a SIB (25), which incorporated the boost dose directly into a single plan (84 of 91 patients), and a concomitant IMRT boost, which added separate IMRT fields specifically designed to deliver the boost dose to the lumpectomy site on top of the ipsilateral whole breast dose (7 of 91 patients). The initial SIB approach used two to four IMRT fields. When more than two fields were chosen, a noncoplanar beam arrangement was used, most typically using three fields, inclusive of a medial field without couch rotation, combined with two lateral fields, each accompanied by a 10–20 couch rotation (Fig. 2). The boost was integrated directly into the IMRT optimization and treatment. For a medially located tumor bed, the beam arrangement can be flipped from that depicted in Fig. 2. Normal tissue constraints were designed so that no more than 10% of the heart and lung volume was allowed to receive >18 and >20 Gy, respectively. A 2-cm skin flash was added to the IMRT fields in conformance with the institution’s practice of
Fig. 2. Example of beam distribution for three-field intensity-modulated radiotherapy plan with simultaneous integrated boost. Single right anterior oblique medial beam with no couch angle and two left posterior oblique lateral beams, each with 15 couch rotation. Intersection of beams with skin surface shown.
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providing skin flash for standard breast tangent fields to account for daily positioning uncertainties. One disadvantage of relying solely on IMRT planning to achieve the intended dose distribution was the generation of dose distributions that often required IMRT field fluence editing to eliminate high-dose areas. In addition, the use of multiple, large, tangentlike IMRT fields with couch rotations extended the volume of nonbreast tissue included in the treatment fields superiorly and inferiorly. For these reasons, the technique evolved to a concomitant boost approach in the last 7 patients. Standard non-IMRT tangent fields were used to deliver the dose to the whole breast, supplemented daily by noncoplanar IMRT boost fields. The boost fields were required to enter and exit the breast within the volume of tissue included by the tangent fields, preventing the inclusion of additional nonbreast tissue within the irradiated volume. The tangential plans were created using two or three fields, with enhanced dynamic wedges as necessary. These plans were then submitted as a base plan for optimization of the boost fields. The optimization and calculations were performed using Helios/Eclipse software (Varian Medical Systems, Palo Alto, CA). Helios uses a gradient-dependent optimization algorithm to satisfy a given set of dose–volume objectives. In this instance, the constraints and priorities were established for PTV1, PTV2, body, lung, and heart. These values can be dynamically adjusted during optimization to improve the dose distribution beyond the expectations associated with the general set of constraints.
Dose fractionation and radiobiologic rationale for dose selection The linear-quadratic model (26) was used to determine whether the proposed accelerated intensity-modulated RT protocol yields a roughly equal probability of tumor control compared with a standard schedule, without increasing the potential for normal tissue damage. BEDs for the standard and accelerated IMRT schedules were calculated, as previously described (27). These calculations assume full repair takes place during the $24-h interval between fractions. Table 1 lists the BEDs for tumor control, early responses to radiation effects (erythema and desquamation), and late responses
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(telangiectasia and fibrosis). The choices for the a/b values used for these computations have been justified in previous studies (28–33). In addition, the hypofractionated treatment also represents an accelerated protocol in which the total dose is delivered in only 18 days. Therefore, little or no tumor proliferation is likely to occur during the course of this proposed treatment compared with during the standard treatment in which it is probable that tumor proliferation will take place, decreasing the chance of tumor control (34–37). As presented in Table 1, the inclusion of a cell proliferation correction factor produces small decreases in the BEDs for the standard treatment. Therefore, taking into consideration tumor proliferation during treatment, the accelerated IMRT schedule results in BED values greater than, or equal to, the standard treatment for a/b values of either 2 or 4 Gy and only slightly lower values using a 10-Gy a/b value.
RESULTS Table 2 lists the dosimetric results of this study for the IRBV for which 100% of the prescribed dose was 40.5 Gy. The data are reported as the percentage of volume that received 95% of 40.5 Gy or 100%, 110%, 120%, and 125% of 40.5 Gy. In this way, the dose coverage and hot spots are both evident. The dose coverage for PTV2 is summarized in Table 3, with the volume data for PTV1 and PTV2. The data are reported as the dose covering 95% and 90% of PTV2. The prescription dose for PTV2 was 48 Gy. The PTV2/PTV1 ratio, the percentage of the breast occupied by the tumor bed PTV, was 4–55%, with 10 of 91 patients demonstrating a PTV2 volume >25% of the whole breast volume. The mean volume of whole breast (PTV1) that received a minimum of 48 Gy (V48) was 27.2%. Ideally, PTV2 and V48 would coincide. A gauge of the conformality of the population of plans is a measure of how well the fractional volume of breast receiving >48 Gy mimicked the relative volume statistics. An index of conformality was defined as the volume enclosed by the prescription isodose surface to
Table 1. Biologically equivalent doses for AIMRT schedule as function of a/b ratios Normal tissue response Fibrosis Telangiectasia Erythema Desquamation
Tumor control Tumor Tumor* Tumor Tumor* Tumor Tumor*
a/b (Gy)
Standard schedule (2 Gy 23 fractions in 39 d)
AIMRT schedule (2.7 Gy 15 in 18 d)
2 4 8 11
92 Gy2 69 Gy4 58 Gy8 54 Gy11
95 Gy2 68 Gy4 54 Gy8 50 Gy11
a/b (Gy)
Standard schedule (2 Gy 30 fractions in 39 d)
AIMRT schedule (3.2 Gy 15 fractions in 18 d)
2 2 4 4 10 10
120 Gy2 116 Gy2 90 Gy4 86 Gy4 72 Gy10 68 Gy10
125 Gy2 125 Gy2 86 Gy4 86 Gy4 63 Gy10 63 Gy10
Abbreviation: AIMRT = accelerated intensity-modulated radiotherapy. * Taking into account cell proliferation during treatment course.
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Table 2. Dosimetric summary for ipsilateral residual breast volume for 91 patients treated with prone AIMRT IRBV receiving indicated percentage of prescription dose (40.5 Gy) (%) Median SD Mean Minimum Maximum
V95 (38.5 Gy)
V100 (40.5 Gy)
V110 (44.6 Gy)
V120 (48.6 Gy)
V125 (50.6 Gy)
98.3 2.5 97.6 87.8 100.0
94.8 4.9 93.6 74.4 100.0
33.4 15.2 36.0 4.3 92.8
13.2 9.0 14.1 0.8 48.5
1.2 3.3 2.6 0 13.3
Abbreviations: AIMRT = accelerated intensity-modulated radiotherapy; IRBV = ipsilateral residual breast volume (IRBV = PTV1 PTV2); V95, V100, V110, V120, V125 = % volume of whole breast receiving minimum of 95%, 100%, 110%, 120%, and 125%, of prescription dose, respectively; SD = standard deviation; PTV1 = breast tissue; PTV2 = tumor bed + 1-cm expansion.
the target volume: PITV = V48 Gy/VPTV2, where V48 Gy is the volume enclosed by the 48-Gy isodose surface and VPTV2 is the volume of the boost structure, PTV2. The mean ratio of the 48-Gy volume to the PTV2 was 1.9 (median, 1.8; range, 0.9–4.2). The median volume coverage of PTV2 with 48 Gy was 97.2% (range, 78–100%). The median dose that covered 95% of PTV2 was 48.2 Gy (range, 44.6–49.5). A 95% dose coverage to 95% of the PTV2 was achieved in 88 of 91 cases. The overall plan dose maximum had a median value of 128.9%. The PTV2 prescribed dose of 48 Gy was 118.5% greater than the whole breast prescribed dose of 40.5 Gy. As such, the 128.9% dose maximum (52.2 Gy) represented an increase of approximately 10% more than the PTV2 prescription dose of 48 Gy. In Table 4, the data are organized according to three planning strategies. Of the 91 patients, 21 were treated using three or four noncoplanar SIB fields, 63 were treated with two SIB fields, and 7 were treated with the concomitant boost approach. For all three categories, the median dose that covered 95% of PTV2 was >48 Gy and the median index of conformality, PITV, was #2. Although the concomitant boost approach had the greatest median PITV, it offered the best PTV2 coverage, with the smallest high-dose region and dose maximum. The overlap between the results of the three techniques is sufficient to support dosimetric equivalence. The heart and lung doses are summarized in Table 5. The minimal dose covering 5% of the organ (D5) and the volume that received >18 Gy for the heart and >20 Gy for the ipsilateral lung are reported. The maximal volume that received 18 Gy to the
heart and 20 Gy to the lung was 4.7% and 7.2%, respectively, observing the 10% limit required by the protocol. The median volume of the heart that received a minimum of 18 Gy was reported for left-sided breast cancers only and was 0.5%. No measurable volume of the heart received >18 Gy for right-sided breast cancers. The median D5 for the heart for all 91 patients was 2.0 Gy, with a maximum of 10.5 Gy. The median volume of the ipsilateral lung that received $20 Gy was 0.8%. The median D5 for the ipsilateral lung was 3.0 Gy, with a maximum of 29.6 Gy. In 4 of the 91 accrued patients, 5% of the ipsilateral lung volume received >20 Gy; however, as stated previously, no instances occurred in which >10% of the lung volume exceeded the protocol limit of 20 Gy. The median values for the IRBV, PTV2, heart volume, and lung volume are displayed in a dose–volume histogram style plot (Fig. 3). The values were connected by a drawn dotted line to help depict the shape of the dose–volume histograms and facilitate the interpretation of the relative relationships of the tabulated values. The global dose maximum is also included and used as the upper dose limit for the dose– volume histogram plot of PTV2. The volume of residual breast that received 120% of the prescription dose was chosen as a measure of how much of the boost dose ‘‘leaked’’ into the surrounding breast tissue. The total dose to the boost site was 48 Gy (118.5% of the prescription dose). Therefore, it was not surprising to detect a margin of high dose surrounding the PTV2. Figure 4 illustrates the correlation of the volume of the whole breast occupied by PTV2 to the volume of high-dose regions in the
Table 3. PTV2 dose coverage and volume summary for 91 patients treated with prone AIMRT PTV2
Median SD Mean Minimum Maximum
PTV1 (cm3)
PTV2 (cm3)
PTV2/PTV1 (fractional volume)
D95 (Gy)
D90 (Gy)
641.6 540.0 765.7 120.6 2743.8
81.6 94.5 111.7 21.2 604.5
0.14 0.09 0.16 0.04 0.55
48.24 0.83 48.12 44.63 49.46
48.64 0.64 48.56 46.37 49.90
Abbreviations: D95 and D90 = minimal dose covering 95% and 90% of organ, respectively; other abbreviations as in Table 2.
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Table 4. Variation of dosimetric parameters as function of treatment technique 3–4-Field SIB
2-Field SIB
Concomitant boost
Patients (n) PTV2 D95 (Gy) PITV IRBV, 40.5 Gy (%) IRBV, 48 Gy (%) Dose maximum (Gy)
21 48.13 (0.93) 1.52 (0.67) 92.0 (5.7) 7.4 (7.0) 53.52 (1.3)
63 48.32 (0.82) 1.81 (0.57) 95.3 (4.7) 14.3 (9.1) 52.02 (1.12)
7 48.48 (0.35) 2.01 (0.56) 94.5 (2.8) 6.2 (7.6) 50.83 (0.64)
80
Volume (%)
Parameter
A number of investigators have discussed the advantages of IMRT for breast homogeneity and of the rationale for integrating the boost into the daily treatment sessions (8, 22, 23). A hybrid approach was suggested to make the process more efficient and eliminate certain inhomogeneities that can arise in inverse-planned opposed tangents (8–10). With dose gradients of 119% intentionally inserted into regions of the breast (48 Gy/40.5 Gy), the risk of dose-related
Table 5. Dosimetric results for heart and ipsilateral lung Ipsilateral lung
Median SD Mean Minimum Maximum
Heart*
0
0
10
20
30
40
50
60
Dose (Gy)
Fig. 3. Median dose–volume histogram values plotted. Solid triangles represent dose–volume histogram for residual breast (planning target volume 1 [breast tissue] planning target volume 2 [tumor bed plus 1-cm expansion]); open triangles, planning target volume 2 values; solid diamonds, heart values; and open diamonds, lung values. Median dose maximum of 52.2 Gy also included. Lines included only to aid in individual dose–volume histogram values.
complications becomes a central consideration during planning. The three-field SIB technique initially adopted showed overall hot spots of 130%. As seen in Table 1, such a hot spot could be quite relevant when larger fractions are used, with greater BEDs for fibrosis associated with an accelerated regimen. Recent studies have suggested a relationship between the development of Grade 3 fibrosis and certain ATM gene sequences (38, 39). It is possible that carriers of specific genetic profiles could be particularly susceptible to the risk of complications. To investigate this association
80 70
% Volume (V48)
DISCUSSION
40
20
Abbreviations: SIB = simultaneous integrated boost; PITV = index of conformality (V48/VPTV2); V48 = volume of whole breast receiving minimum of 48 Gy; other abbreviations as in Table 2. Data presented as median with SD in parentheses.
whole breast and residual breast. Although a relationship between this ratio and the whole breast volume receiving a minimum of 48 Gy was apparent, no clear relationship was detectable with the IRBV once the PTV2 was excluded. The dose to the ipsilateral lung was also considered separately for right- and left-sided lesions (Fig. 5). The D5 values for each case are presented and grouped by right or left side. The two groups appeared similar, suggesting that the lung doses were only minimally decreased in left-sided breast cancers, as a result of the sparing dictated by the proximity of the heart in these patients. The median value was 2.6 Gy for the left breast cases and 3.5 Gy for the right breast cases.
60
60 50 40 30 20 10
D5 (Gy)
V20 Gy (%)
D5 (Gy)
V18 Gy (%)
3.0 5.3 4.5 0 29.6
0.8 1.6 1.3 0 7.2
2.0 2.2 2.7 0 10.5
0.5 1.3 1.0 0 4.7
Abbreviations: D5 = minimal dose covering 5% of organ; V20 Gy and V18 Gy = volume that received >20 Gy (lung) and >18 Gy (heart), respectively; SD = standard deviation. Values expressed as dose for D5 and percentage of volume for V18 Gy and V20 Gy. * Women with left-sided breast cancers only included in analysis for V18 Gy to heart.
0 0.00
0.10
0.20
0.30
0.40
0.50
0.60
Ratio of PTV2 to PTV1
Fig. 4. Volume of the entire breast receiving a dose >48 Gy (V48) presented as function of fractional volume of breast occupied by tumor bed plus 1-cm expansion (planning target volume 2 [PTV2]; solid triangles). Because a greater fraction of breast becomes occupied by boost volume (PTV2), a greater percentage of breast received $48 Gy, as expected. Similar data shown for residual breast (open triangles). Percentage of residual breast volume receiving a minimum of 48 Gy did not increase as the fractional volume occupied by PTV2 increased. Median percentage volume receiving $48 Gy was 13.2% for the residual breast volume and 27.2% for the whole breast (PTV1).
D5: Dose at 5% Volume Level for DVH of Ipsilateral Lung (Gy)
Prone breast accelerated IMRT d J. K. DEWYNGAERT et al. 35.00 30.00 25.00 20.00 15.00 10.00 5.00 0.00
0
10 20 30 40 50 Case Number for Right Breast and Left Breast
60
Fig. 5. Lung doses encompassing 5% of ipsilateral lung (D5) with accelerated intensity-modulated radiotherapy to the breast. Data segregated into left-sided lesions (closed triangles) and right-sided lesions (open triangles).
further, this study included a collection of blood samples for polymorphism studies of candidate genes. Because the concomitant boost approach tended to be associated with the lowest dose maximum and the smallest volumes of high dose, we eventually migrated to this approach. This choice was supported by the relative ease of planning a concomitant boost plan compared with planning the SIB plans. Generally, the conformality index should be a measure not just of how well the isodose conforms to its target, but also of the high-dose volume of nontarget tissue that surrounds the target. Considering the data once all three planning approaches were combined, the median index of conformality for PTV2 was 1.80. When analyzed separately, they ranged from 1.52 to 2.01 (Table 4). Values >1.0 indicate dose volumes larger than the target volume. From the radiosurgery data, values between 1 and 2 are considered acceptable (40). Although the concomitant boost approach has the greatest conformality index (extra volume of high dose), it has the lowest fractional IRBV receiving the high dose. With the limitation of the small number of patients receiving the concomitant boost technique, the median fractional volume of the breast occupied by the PTV2 was 64% compared with the SIB techniques. This reflects a smaller median PTV2. Small increases in the conformality index for the concomitant boost technique compared with the other techniques would represent a much smaller absolute IRBV. Three cases had a conformality index >3.0. For each case, the target occupied a large cross-sectional area in the beams’ eye view, with a narrow lateral extent. In these instances, it is difficult to maintain a low conformality index because of the table rotation limitations with the patient lying prone. Data have suggested that cardiac toxicity can be associated with the volume of heart in the field and that increased mortality from lung cancer deaths can be similarly associated with the dose received by the lung (41–45). With prone positioning, the breast tissue falls away from the chest wall. Typically, the heart and lung could be excluded from the treatment fields, thus maintaining doses to the lung and heart
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well below our target values. An important argument often used in support of partial breast irradiation is lung and heart sparing. The Radiation Therapy Oncology Group partial breast protocol 0413 limited <15% of the ipsilateral lung to receive >30% of the prescribed dose (11.5 Gy) and <5% of the heart volume to receive >40% of the prescribed dose (15.4 Gy) for left-sided lesions (46). For right-sided lesions, the heart constraint decreases to <5% of the volume to receive >5% of the prescribed dose (1.9 Gy). The protocol calls for 38.5 Gy to be delivered in 10 fractions within 5 days. The data presented here were not parsed at the 15% volume level for the ipsilateral lung doses nor planned for the partial breast; however, 90% of our cases were able to meet the 11.5-Gy dose constraint (Fig. 5) at the more stringent 5% volume level, while treating the whole breast and delivering a boost to the tumor cavity. For the left-sided lesions, all the plans met the 15.4-Gy dose constraint for the heart, with a median value of 2.0 Gy (range, 0–10.5 Gy). For the right-sided lesions, the median value for 5% of the heart was 1.5 Gy, with >92% (37 of 40) of the cases meeting the Radiation Therapy Oncology Group 1.9-Gy constraint. Figure 5 also demonstrates similar results for lung dosimetry, independent of laterality. The low doses associated with scattered radiation from combined chemoradiotherapy to the breast have been linked to an increased risk of leukemia (47, 48). Woo et al. (49) considered the factors that lead to an increase in scatter dose to different parts of the body. The most significant factor was the use of physical wedges. An inverse relationship with cup size was established for doses to the contralateral breast. No physical wedges were used in this study and, at New York University hospitals, have not been used for >10 years. The dose to the contralateral breast due to scatter from the treated breast remains to be studied for women in the prone position. Supplementing the dose to the tumor bed, either as an integrated IMRT boost or as a separate concomitant boost, is dependent on the ability to properly target the tumor bed. The strategy of integrating the boost dose into the daily fractionation also requires that the target location and size maintain stability during the RT course. For the present work, the seroma seen on CT was considered a surrogate for the tumor bed. Oh et al. (50) examined the change in the excision cavity after a RT course by comparing a CT scan at the end of treatment with that obtained at simulation. Although they observed minimal changes in the whole breast volume, they observed a dramatic reduction in the size of the cavity during the treatment course (22% mean reduction). It is likely that modification of the cavity on the basis of the volume visualized at simulation results in overestimation of the volume assigned to PTV2. In addition, the accuracy of targeting is hampered by interand intrafraction changes. Recent evidence has suggested that the respiratory-associated movement of the breast is only 1–2 mm during treatment for patients in the prone position (51, 52). We are currently studying the interfraction changes that occur in the prone position through an application of cone-beam CT.
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I. J. Radiation Oncology d Biology d Physics
Finally, none of the patients in this trial also underwent treatment simulation in the supine position, making it impossible to compare the effect of the setup on the IMRT results. The preliminary results of a study by Parhar et al. (18) that compares the effect of positioning, prone versus supine, on the dose to the lung and heart suggest that the prone setup achieves better normal tissue sparing for most patients. CONCLUSION The results of the present study have shown that an accelerated RT regimen to the whole breast with an integrated boost in the prone position is feasible. Positioning the
Volume 68, Number 4, 2007
patients prone enables sparing of the lung and heart, generally to less than levels considered acceptable for partial breast RT (46). The addition of separate and smaller IMRT boost fields integrated with non-IMRT tangent fields was a more efficient planning method and appeared to offer greater control of the high-dose regions compared with an IMRT-SIB approach. A remaining question is the stability of the high-dose target within the breast. Data have suggested that the seroma decreases in size during RT (50) and that the movement due to respiratory motion is minimal (51, 52). Our on-going study of interfraction setup uncertainties should answer our ability to target high-dose regions to specific regions within the breast.
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