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Three-Year Outcomes of Breast Intensity-Modulated Radiation Therapy With Simultaneous Integrated Boost
Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 2, pp. 523–530, 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2009.05.042
CLINICAL INVESTIGATION
Breast
THREE-YEAR OUTCOMES OF BREAST INTENSITY-MODULATED RADIATION THERAPY WITH SIMULTANEOUS INTEGRATED BOOST MARK W. MCDONALD, M.D., KAREN D. GODETTE, M.D., DAISY J. WHITAKER, C.M.D., LAWRENCE W. DAVIS, M.D., M.B.A., F.A.C.R., AND PETER A. S. JOHNSTONE, M.D., F.A.C.R. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA Purpose: To report our clinical experience using breast intensity-modulated radiation therapy with simultaneous integrated boost (SIB-IMRT). Methods and Materials: Retrospective review identified 354 Stage 0 to III breast cancer patients treated with SIBIMRT after conservative surgery between 2003 and 2006. The most common fractionation (89%) simultaneously delivered 1.8 Gy to the ipsilateral breast tissue and 2.14 Gy to the resection cavity, yielding a breast dose of 45 Gy (25 fractions) and cavity dose 59.92 Gy (28 fractions), biologically equivalent for tumor control to 45 Gy to the breast with sequential 16-Gy boost (33 fractions). Results: A total of 356 breasts in 354 patients were treated: 282 with invasive breast cancer, and 74 with ductal carcinoma in situ (DCIS). For left breast radiation, median cardiac V15 was 2.9% and left ventricular V15 1.7%. Median follow-up was 33 months (range, 4–73 months). Acute toxicity was Grade 1 in 57% of cases, Grade 2 in 43%, and Grade 3 in <1%. For invasive breast cancer, the 3-year overall survival was 97.6% and risk of any locoregional recurrence was 2.8%. For ductal carcinoma in situ, 3-year overall survival was 98% and risk of locoregional recurrence 1.4%. In 142 cases at a minimum of 3 years follow-up, global breast cosmesis was judged by physicians as good or excellent in 96.5% and fair in 3.5%. Conclusions: Breast SIB-IMRT reduced treatment duration by five fractions with a favorable acute toxicity profile and low cardiac dose for left breast treatment. At 3 years, locoregional control was excellent, and initial assessment suggested good or excellent cosmesis in a high percentage of evaluable patients. Ó 2010 Elsevier Inc. Breast cancer, IMRT, Simultaneous integrated boost, Toxicity, Cosmesis.
INTRODUCTION
serving therapy (6, 7). The belief of some referring physicians that the risks of breast RT outweigh the benefits in individual cases appears to be the most common reason for not referring patients for RT (8). Increasing distance to a radiation center is also associated with reduced use of breast RT after BCT, presumably in large part because of the inconvenience of longer commutes for daily treatments during a standard fractionation schedule (9, 10). Refinements in breast RT techniques that are more convenient for patients and promise to minimize acute and late toxicities may result in a greater number of women being appropriately referred for and receiving breast RT. Compared with conventional tangential breast RT, intensity-modulated radiation therapy (IMRT) is a treatment approach that reduces acute skin toxicity, specifically moist desquamation (11–14), the occurrence of which adversely
For both invasive breast cancer (IBC) and ductal carcinoma in situ (DCIS), breast radiation (RT) is an integral component of breast-conserving therapy (BCT) that has shown a local tumor control benefit in several randomized trials and, for IBC, an overall survival benefit in one comprehensive meta-analysis (1). Conventional breast RT is delivered to the whole breast with tangential breast fields, typically over the course of 5 weeks with five daily fractions per week. Total treatment time may extend from 6 to 7 weeks (2), as most women receive an additional radiotherapy boost to the resection cavity to further improve local tumor control, as demonstrated in two randomized studies for IBC (3, 4) and as suggested in a retrospective analysis for DCIS (5). Despite its proven benefit, a substantial minority of patients do not receive breast RT as a component of breast conReprint requests to: Karen D. Godette, M.D., Emory University School of Medicine, Winship Cancer Institute, Department of Radiation Oncology, 1365 Clifton Road NE, Atlanta, GA 30322. Tel: (404) 778-3473; Fax: (404) 778-3670; E-mail: karen@radonc. emory.org Drs. McDonald and Johnstone are currently at the Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN.
Presented in part at the 50th Annual Meeting of the American Society for Radiation Oncology, Boston, Massachusetts, September 21–25, 2008. Conflict of interest: none. Received Jan 24, 2009, and in revised form May 8, 2009. Accepted for publication May 13, 2009.
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affects patient quality of life (12, 15). Early randomized data showed improved late cosmesis with breast IMRT (16), and risk modeling suggested that breast IMRT decreases the probability of late normal tissue complications (17, 18). At Emory University School of Medicine, we began using breast IMRT in 1999, and have previously published our experience with a forward planned technique using dynamic multileaf collimators (DMLC) for tissue compensation (11). In 2003, we transitioned to a multi-beam inverse planned IMRT technique using a simultaneous integrated boost (SIB) to the resection cavity (SIB-IMRT). Although the aim of most breast IMRT techniques is to minimize target inhomogeneities, a breast SIB technique exploits and shapes inhomogeneity to provide differential dosing to the whole breast and the resection cavity. Providing a greater dose per fraction to the resection cavity than to the remainder of the breast allows the traditional sequential boost to be eliminated, thereby shortening the treatment course duration. The radiobiologic implications of breast SIB have been detailed (19) and the dosimetry has been shown to be superior to sequential external beam breast boost techniques (20, 21). This article presents our clinical experience with breast SIB-IMRT, with a focus on acute toxicity, late cosmesis, normal tissue dose, risk of locoregional recurrence (LRR), and overall survival (OS). METHODS AND MATERIALS Patient selection and evaluation Treatment records of The Emory Clinic and Emory University Hospital Midtown were evaluated to identify patients with Stage 0 to III breast cancer receiving breast RT following conservative surgery between January 2003 and December 2006. Patients with distant metastatic disease at presentation, those treated after mastectomy, and male patients were not included. Institutional review board approval was obtained for this analysis. All patients underwent standard staging evaluation after diagnosis and were staged according to the 6th edition of the American Joint Committee on Cancer (22). Patients had routinely scheduled multi-disciplinary follow-up with interval history and physicals and breast imaging according to nationally recognized schedules (23). During the study period, the simultaneous integrated boost technique was our standard institutional treatment approach for intact breast radiotherapy, and no patient or disease characteristics were considered for treatment with this approach. All patients provided written informed consent for treatment, without special consideration of the fractionation schedule employed, as the maximum dose was 2.4 Gy to a portion of the breast, within the range of clinical experience.
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Systemic therapy In accordance with consensus guidelines and available evidence at the time, patients at sufficient risk for distant metastasis were offered adjuvant chemotherapy, whereas those with hormone receptor positive breast cancer generally received adjuvant endocrine therapy with tamoxifen or aromatase inhibitors (23–24). Trastuzumab was usually added for patients with her-2-neu–positive IBC. Preoperative chemotherapy was generally offered to facilitate breast conservation in patients with tumors of a size or in a location that made breast-conserving surgery unlikely without a reduction in tumor size. Sentinel lymph node biopsy and/or axillary nodal dissection was generally performed before initiation of neoadjuvant chemotherapy.
Radiation Radiation therapy was typically initiated within 4 weeks after completion of all surgery and chemotherapy. A computed tomography (CT) scan was obtained for treatment planning in all patients, with 0.25-cm slices from the mid-neck to several centimeters caudal to the breasts. Patients underwent scanning in the supine position with the ipsilateral arm abducted, using a ‘‘T’’ stabilization bar. For larger-breasted women, a slant board was generally used at the discretion of the attending radiation oncologist. At the time of simulation, the physician placed radiopaque wire to encompass all clinically palpable breast tissue and to demarcate the surgical scar to assist in planning the boost. Beginning in 2005, all patients underwent daily localization with kV-kV image matching before treatment.
Definition of treatment volumes We have previously presented our SIB-IMRT technique (28). The ipsilateral whole breast was defined as the breast clinical target volume (CTVbreast), which was contoured by the physician in Eclipse treatment planning software (Varian Medical Systems, Palo Alto, CA) using both the radiopaque wire placed at simulation and adjustments in CT window level. The breast planning target volume (PTVbreast) equaled the CTVbreast with modification of the optimized plan to account for anterior respiratory motion, as described below. The PTVbreast did not include the pectoralis muscles or chest wall, nor the axillary nodal regions, and was auto-cropped to exclude tissue within 3 mm of the outer body contour. The tumor resection cavity was defined as the boost clinical target volume (CTVboost), which was contoured on CT based on postsurgical architectural distortion and surgical clips and was correlated with the surgical scar, operative, and pathology reports. Because the boost prescription isodose typically extended 0.3 to 0.5 cm beyond the CTVboost, the boost planning target volume (PTVboost) was equal to the CTVboost. A boolean operation was then used to subtract the PTVbreast with additional 1 cm margin from the body contour to create a single avoidance structure for plan optimization. The ipsilateral lung was auto-contoured and, for left-sided breast treatment, the cardiac silhouette and/or left ventricle were manually contoured.
Surgery
Treatment planning
Patients underwent conservative surgery with pathologic evaluation according to recognized practice guidelines (24). Re-excision for close or positive margins was performed in accordance with patient and surgeon preferences. Margins were categorized as positive if the pathology report noted the presence of tumor cells at the inked margin of the specimen, close if tumor cells were present within 0.2 cm of the inked margin, and negative if tumor cells were at least 0.2 cm from the inked margin.
Two medial and two lateral nonopposed tangential fields were designed to treat the PTVbreast. The gantry separation between ipsilateral fields ranged from 5 to 10 . Treatment fields were modified to completely avoid the contralateral breast and to minimize the volume of lung tissue in the field. Two additional fields were created to encompass the PTVboost, with field configurations customized to the location of the patient’s resection cavity, generally in a cranio-caudal direction or occasionally with an appositional field.
IMRT with integrated boost for breast cancer d M. W. MCDONALD et al.
After optimization was complete, fluence maps were manually edited to add 2 cm of ‘‘virtual flash’’ anterior to the breast to account for respiratory motion. When a supraclavicular field was prescribed, an anterior half-beam blocked field was matched to the breast IMRT field at the level of the inferior edge of the sternoclavicular junction. This field was treated with 6-MV photons, to a dose of 45 to 50 Gy in 1.8- to 2-Gy fractions, typically prescribed to a depth of 3 to 4 cm. The ipsilateral internal mammary nodes were not electively treated. Most cases (n = 319) were treated with the same SIB fractionation schedule, hereafter termed SIB-A. In this schedule, 25 fractions of 1.8 Gy to PTVbreast (45 Gy total) and 2.14 Gy to PTVboost were given, followed by a dedicated cavity boost of three fractions of 2.14 Gy, bringing the total dose to PTVboost to 59.92 Gy. Two other fractionation schedules were used during the study time period. In SIB-B (n = 25), 28 fractions of 1.8 Gy to PTVbreast (50.4 Gy total), and 2.14 Gy to PTVboost (59.92 Gy total) were delivered simultaneously. In SIB-C (n = 12), 25 fractions of 1.8 Gy to PTVbreast (45 Gy total) and 2.4 Gy to PTVboost (60 Gy total) were delivered simultaneously. The fractionation schedules were used sequentially, independent of patient factors, as we optimized dosimetric parameters.
Radiobiologic rationale To compare SIB-IMRT fractionation with conventional sequential boost schedules, a biologically equivalent dose (BED) was calculated using the linear-quadratic (LQ) model (29): BED ¼ D½1 þ d=ða=bÞgTt =a where D is the total dose, d is the dose per fraction, a and b are LQ parameters, Tt is the total treatment time in days, and g = ln(2)/Tpot, where Tpot is the potential doubling time. The same LQ parameters and Tpot chosen by Guerrero et al. (19) were used, where Tpot = 15 days and a = 0.3 Gy1, as initially derived from clinical data and in vitro measurements (30, 31). In comparison of fractionation schedules for tumor control, an a/b of 10 was used. In comparing schedules for late normal tissue effects, a/b was set at 3 and no treatment time correction was used (29). Table 1 delineates the three SIB fractionation schedules used with comparable sequential schedules. Because SIB-A and SIB-B both gave 28 fractions of 2.14 Gy to the boost volume, the BED for tumor control and late effects are the same and are equivalent to a sequential strategy of 25 fractions of 1.8 Gy to the whole breast followed by eight fractions of 2 Gy to the boost. As previously demonstrated by Guerrero et al. (19), SIB-C was equivalent to 25 fractions of 1.8 Gy to the whole breast followed by 10 fractions of 2 Gy for the boost.
Assessment of toxicity During treatment, acute toxicity was assessed by the physician at on-treatment checks at least weekly. Acute toxicity was retrospectively graded according to the Common Terminology Criteria for
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Adverse Events version 3 (32) based on the highest grade toxicity described in the interval from start of treatment to 4 weeks after completion. Documentation of acute radiation toxicity was the focus of these weekly on-treatment notes, the final treatment summary, and the first follow-up visit, which occurred 1 month after completion of treatment. All these notes were reviewed for descriptions of patientreported symptoms and physical examination findings including skin erythema, dry or moist desquamation, and breast edema. Patient charts were also reviewed for physician assessment of global breast cosmesis, which was graded according to the Harvard criteria, where good or excellent outcomes reflected minimal or no identifiable radiation changes in the treated breast, readily observable significant changes were scored as fair cosmesis, and severe radiation effects reflected a poor cosmetic score (33).
Statistical analysis Follow-up time was calculated from the onset of definitive therapy, either the date of first definitive surgery or the start date of neoadjuvant chemotherapy for those patients treated with preoperative chemotherapy. Only the site of first failure was considered for analysis, using one of the following categories: locoregional recurrence (LRR), contralateral breast tumor recurrence (CBTR), or distant metastasis (DM). The category of LRR included recurrence in the ipsilateral breast, axilla, internal mammary nodes, or ipsilateral supraclavicular space. Overall survival (OS), and risk of LRR, CBTR, and DM were calculated using the method of Kaplan and Meier (34). Patients with synchronous bilateral breast cancer were not scored as having CBTR or included in the number at risk for CBTR, and were included only once in analysis of OS and risk of DM. Statistical analysis was performed using Stata version 9.2 software (StataCorp, College Park, TX).
RESULTS Patient characteristics Between January 2003 and December 2006, 356 breasts were treated in 354 patients: 282 with IBC and 74 with DCIS. Included in analysis were 2 patients with synchronous bilateral breast cancer. Patient characteristics are listed in Table 2. For all patients, the median PTVbreast was 732 cc (range, 80–2931 cc), with a median PTVboost of 23.2 cc (range, 2.6–439 cc). The median ipsilateral lung volume receiving 20 Gy or more (V20) was 10.6% (range, 0–27%). Analyzing left breast cases only (n = 168), the median value for mean heart dose was 2.6 Gy (range, 0.6–7.8 Gy), whereas the median volume of heart receiving 15 Gy or more (V15) was 2.9% (range, 0–17.4%). The median value for the mean left
Table 1. Comparison of fractionation schedules used Schedule name
No.treated
Fractional whole breast
Fractional boost
Nominal total dose
Total no. fractions
SIB-A SIB-B Comparable sequential schedule SIB-C Comparable sequential schedule
319 25 —
1.8 Gy 25 1.8 Gy 28 1.8 Gy 25
2.14 Gy 28 2.14 Gy 28 2 Gy 8
59.92 Gy 59.92 Gy 61 Gy
12 —
1.8 Gy 25 1.8 Gy 25
2.4 Gy 25 2 Gy 10
60 Gy 65 Gy
Abbreviation: BED = biologically equivalent dose.
BED tumor control
BED late effects
28 28 33
67.0 Gy10 67.0 Gy10 65.5 Gy10
102.6 Gy3 102.6 Gy3 98.7 Gy3
25 35
69.5 Gy10 69.4 Gy10
108.0 Gy3 105.4 Gy3
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Table 2. Patient characteristics (Continued)
Table 2. Patient characteristics Patients with IBC (n = 282) Age (y) Median Range Premenopause Postmenopause Breast Right Left Stage I II III Grade 1 2 3 Not reported Estrogen receptor Positive Negative Her-2-neu Positive Negative Unknown Triple negative Margin Negative Close Positive pLNs (+) 0 1–3 $4 Not assessed ENE NA CTX pCR rate Adj CTX Adj HT Fractionation SIB-A SIB-B SIB-C Patients with DCIS (n = 74) Age (y) Median Range Premenopausal Postmenopausal Breast Right Left Tumor size Median Range Grade 1 2 3 Necrosis present Margin Negative Close Positive
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55 24–89 85 (30%) 197 (70%) 152 (54%) 130 (46%) 171 (61%) 96 (34%) 15 (5%) 77 (27%) 100 (35%) 92 (33%) 13 (5%)
Estrogen receptor Positive Negative Not assessed Adj HT Yes No Fractionation SIB-A SIB-B SIB-C
58 (78%) 6 (8%) 10 (14%) 49 (66%) 25 (34%) 68 (92%) 3 (4%) 3 (4%)
Abbreviations: Adj CTX = adjuvant chemotherapy; Adj HT = adjuvant hormonal therapy; DCIS = ductal carcinoma in situ; ENE = extranodal extension in involved lymph nodes; NA CTX = neoadjuvant chemotherapy; not assessed = no lymph node dissection done; pCR rate = pathologic complete response to neoadjuvant chemotherapy; pLNs (+) = number of pathologically involved lymph nodes; SIB = simultaneous integrated boost.
202 (72%) 80 (28%) 55 (20%) 210 (74%) 17 (6%) 60 (21%) 237 (84%) 42 (15%) 3 (1%) 211 (75%) 52 (18%) 10 (4%) 9 (3%) 17/62 (27%) 44 (16%) 11/44 (25%) 104 (37%) 173 (61%) 251 (89%) 22 (8%) 9 (3%) 56 38–85 15 (20%) 59 (80%) 36 (49%) 38 (51%) 0.7 cm 0.1–5 cm 7 (9%) 33 (45%) 34 (46%) 55 (74%) 61 (82%) 10 (14%) 3 (4%) (Continued)
ventricle dose was 2.4 Gy (range, 0.4–14.7 Gy), whereas the median V15 for the left ventricle was 1.7% (range, 0–37.5%). Outcomes Acute toxicity and cosmesis. In 353 of the 356 treated cases (99%), data were available to grade acute toxicity. The acute skin toxicity was Grade 0 in four treated breasts (1%), Grade 1 in 196 (56%), Grade 2 in 152 (43%), and Grade 3 in one (<1%). Three patients (<1%) developed acute breast cellulitis. An assessment of global breast cosmesis at a minimum of 3 years of follow-up was available in 142 cases (40%). Among these, 96.5% were judged as good or excellent, while 3.5% were considered fair, with no patients judged to have a poor cosmetic outcome. Survival, local and distant failure. The median follow-up time for all patients was 33 months (range, 4–73 months). Among the 282 breasts treated for IBC, there were eight ipsilateral breast tumor recurrences, two ipsilateral axillary nodal recurrences, one simultaneous axillary and supraclavicular recurrence, and one ipsilateral supraclavicular recurrence simultaneous with distant metastases. The Kaplan-Meier risk of any LRR at 3 years was 2.9%, with an OS of 97%. There were three CBTR for a 3-year risk of 0.4%. Nine patients had DM as a component of first failure, yielding a 3-year risk of 2.7%. Among the 74 breasts with DCIS, there was one ipsilateral breast recurrence with a Kaplan-Meier risk of any LRR at 3 years of 1.4%, and an OS of 98%. There were no instances of CBTR or DM observed in the patients with DCIS. Analysis of local failures. Among the 8 patients with IBC and IBTR, four were in the same quadrant as the primary, three were in separate quadrants from the original tumor, and one recurrence was a diffuse inflammatory breast cancer. Of the four recurrences in the same quadrant, two were more than 2 cm from the lumpectomy site, whereas two recurred adjacent to the original lumpectomy site in breast tissue receiving 50 to 60 Gy in 1 patient and 57 Gy in the other patient.
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dosimetry in selected patients for those with the expertise to offer this modality. Efforts such as inspiratory breath hold, currently used at our institution, may further reduce cardiac dose in treatment of the left breast. Although breast IMRT can improve target homogeneity and reduce dose to normal structures (17, 18), there remains a theoretical increased risk for secondary malignancies (39). Most breast IMRT techniques, including our own, use tangential field arrangements, which reduce the low-dose spread seen in typical multi-directional IMRT field arrangements for other disease sites. However, breast IMRT still requires more monitor units for delivery with the likelihood of more scatter dose. These concerns deserve our continued careful consideration and require long-term follow-up. Our previous evaluation of 121 patients treated with breast IMRT compensation found a 3% rate of secondary malignancy at 7 years, which was not significantly different from the 4% rate observed in a contemporaneous cohort of patients treated with conventional radiation (11). Detecting a difference in the rate of secondary malignancies with breast IMRT would undoubtedly require a substantially larger sample size and still longer follow-up. One of the challenges of inverse-planned breast IMRT is the interobserver and interinstitutional variability in attempts at delineating CT-based target volumes (40, 41). The recent development of Radiation Therapy Oncology Group (RTOG) consensus guidelines and a contouring atlas for breast radiotherapy planning will hopefully improve homogeneity in target definitions and facilitate comparison between future studies. Our institutional PTVbreast did not include all the tissue encompassed in standard tangential breast fields, as it specifically excluded the pectoralis muscles, chest wall, and the axilla. Because of the geometry of tangential fields used, however, the subpectoral lymph nodes and portions of axillary Level I generally still received significant dose. The three axillary nodal recurrences in our series all occurred in tissue that received essentially the same dose as would have been delivered with standard tangents. Our PTVboost was smaller than described by most institutions for sequential boost techniques, being limited to the resection cavity as identified by CT changes and surgical clips. We used this boost volume definition with an understanding
There was one ipsilateral breast tumor recurrence in a patient with DCIS, which recurred immediately anterior to the lumpectomy site in breast tissue that had received 60 to 63 Gy. Among the 3 patients with IBC and a component of axillary recurrence, 2 experienced recurrence in Level I axillary tissue that had received 46 Gy in 1 patient, and 50.4 Gy in the second, and 1 patient in Level II axillary tissue that had received 50.4 Gy. The 2 patients with failure in the supraclavicular fossa had not received supraclavicular radiation. DISCUSSION Several planning studies have investigated SIB-IMRT (19–21, 35), but published clinical experience with breast SIB is limited. Freedman et al. (36) reported their experience with hypofractionated breast IMRT using a simultaneous electron boost in 75 patients. In their report, the hypofractionated regimen was well tolerated, with acute dermatitis comparable to that observed with standard fractionation regimens, although long-term cosmesis data were not yet available. A three-dimensional conformal breast SIB technique was reported by van der Laan et al. (37), with a favorable acute toxicity profile in the first 90 patients treated. Morganti et al. (38) reported on 201 patients treated with SIB-IMRT, including 102 patients treated with the SIB-C fractionation reported here. The acute toxicity observed with the SIB-C fractionation appeared similar to historical controls, and with a median follow-up time of 24 months, locoregional control was excellent. Our report includes the largest reported series of patients treated with breast SIB, as well as one of the largest numbers of patients treated with breast IMRT. Table 3 lists several recent series of breast IMRT or breast SIB that reported ipsilateral lung doses and heart doses for patients with left-sided disease. Because of differences in individual patient anatomy and differences in target volume definitions and fractionation used, direct comparison between studies would be inappropriate, but the normal tissue doses in our experience appear to be comparable to those achieved in these mostly planning studies. None of these studies included comparison to interstitial breast brachytherapy as a boost modality, which may offer more optimal
Table 3. Select published dosimetry Study (Ref)
No. cases
Boost dose
No. fxs
50
None
25
10 20 10 91
45 50 50.4 40.5
None None 66.4 48
25 25 28 15
1.4-2.3 2.3 5.25 2.0
NR 7.2% 12.5% 1.3%
30 356
50.7 45
64.4 59.92
28 28
4.8 2.6
5.5% 10.6%
Year
Technique
BCCA (46)
2006
IMRT
5
UAB (47) UPMC (48) Loyola (20) NYU (35)
2007 2007 2006 2007
IMRT IMRT SIB-IMRT SIB-IMRT
Netherlands(37) Emory
2007 2009
SIB-3DCRT SIB-IMRT
Breast dose
Mean heart dose 12.8
Ipsilateral lung V20 15.1%
Comment Planning study; IMNs included Planning study Planning study Planning study Prone treatment 51 left side breasts 90 patients treated 168 left-side breasts
Abbreviations: fxs = fractions; IMNs = internal mammary lymph nodes; IMRT = intensity-modulated radiation therapy; NR = not reported; Ref = reference; SIB = simultaneous integrated boost; V20 = volume receiving $20 Gy. All doses are given in Gy.
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that the SIB-IMRT technique provides an intermediate dose range gradient around the boost target whereas the boost prescription isodose itself generally extended in a 0.3- to 0.5-cm halo around the PTVboost. Siebers et al. (42) have evaluated the effect of such ‘‘nesting’’ of dose levels inherent in an SIB-IMRT technique and have shown that target volume coverage in the head and neck is minimally influenced by random patient setup errors of up to 5 mm, although the investigators still recommended use of PTV expansions to ‘‘reduce the effect of setup errors in the overall dose evaluation.’’ Additional consideration was given to the difference in BED with SIB-IMRT. If 60 Gy is considered the minimum cumulative boost dose when using a sequential boost schedule, with SIB-A fractionation, 57.7 Gy provided a biologically equivalent dose for tumor control, so that with SIB-IMRT, a slightly larger volume than the prescription boost isodose received the equivalent of 60 Gy given sequentially, providing an additional safety margin. An analysis of the local recurrences seen in our series identified three recurrences adjacent to the resection site, and two of the three received dose comparable to what would have been delivered with a sequential technique using larger boost margins of 1 to 2 cm. Our method of boost target delineation appears clinically effective with our SIB-IMRT technique, with no apparent increase in local recurrences, although strong consideration should be given to the addition of a PTV expansion to the boost CTV. This study was retrospective, with relatively short followup, and cosmetic evaluation was limited to a physician assessment of global breast cosmesis, scored according to the Harvard criteria, with no available patient assessment or photographic record. Although further follow-up is warranted to better assess the ultimate cosmesis in patients treated with SIB-IMRT, long-term follow-up of the Harvard experience showed that excellent cosmesis scores at 3 years were likely to remain excellent, whereas good scores were more likely to improve than to worsen by 7 years of follow-up (33). The SIB-A fractionation used in the majority of patients treated in our series resulted in a five-fraction reduction in treatment duration compared with a sequential boost strategy. This 1-week reduction in treatment is relatively modest compared with other, more aggressively hypofractionated whole-breast treatment schedules. Randomized trials of whole-breast irradiation using fraction sizes of 2.66 to 3.3
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Gy (43–45) found efficacy comparable to that of traditional fractionation, but the widespread adoption of such hypofractionation in the United States has been limited by persistent concerns about late cosmesis, lack of a boost in some schedules, applicability for patients with larger breast sizes, and the lack of data on late cardiac side effects with these larger fraction sizes. Our SIB-A fractionation schedule offers an alternative approach that offers a 1-week shortening in treatment duration while closely conforming the areas of high dose to the tumor resection cavity so that the majority of the breast tissue receives 1.8 to 2 Gy per fraction and cardiac dose is kept low. Accelerated partial breast irradiation (APBI) offers the most hypofractionated treatment schedule currently available, although whole breast irradiation remains the standard of care pending the results of NSABP B-39 / RTOG 0413. Assuming that the efficacy and cosmetic outcomes of APBI are ultimately found comparable to whole-breast regimens, it is likely that whole-breast radiation will remain the treatment of choice for a subset of women based on resource availability or patient characteristics that preclude APBI as currently envisioned. Whole-breast radiation remains essential in successful breast-conservation therapy, and continued attention should be given to radiation planning and delivery techniques that seek to improve convenience and to minimize both acute and late toxicities. CONCLUSION A breast SIB-IMRT technique was developed that reduced treatment duration by 5 fractions compared with an equivalent sequential boost technique. Retrospective analysis of 356 breasts in 354 patients treated with this SIB-IMRT technique found that it was associated with a favorable acute toxicity profile. For left breast tumors, the cardiac volume receiving high dose was minimal. These results were seen in patients treated without a defined CTV to PTV margin expansion, and SIBIMRT to larger treatment volumes may not be associated with the same dosimetry or toxicity profile. At 3 years, the overall survival and locoregional control were excellent for both invasive disease and DCIS. An initial assessment in 142 patients with a minimum of 3 years of follow-up suggested a good or excellent cosmetic result in a high percentage.
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4. Bartelink H, Horiot J, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-Year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007;25:3259–3265. 5. Omlin A, Amichetti M, Azria D, et al. Boost radiotherapy in young women with ductal carcinoma in situ: A multicentre, retrospective study of the Rare Cancer Network. Lancet Oncol 2006;7:652–656. 6. Nattinger AB, Hoffmann RG, Kneusel RT, Schapira MM. Relation between appropriateness of primary therapy for early-stage breast carcinoma and increased use of breast-conserving surgery. Lancet 2000;356:1148–1153.
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7. Hershman DL, Buono D, McBride RB, et al. Surgeon characteristics and receipt of adjuvant radiotherapy in women with breast cancer. J Natl Cancer Inst 2008;100:199–206. 8. Bickell NA, LePar F, Wang JJ, Leventhal H. Lost opportunities: Physicians’ reasons and disparities in breast cancer treatment. J Clin Oncol 2007;25:2516–2521. 9. Athas WF, Adams-Cameron M, Hunt WC, et al. Travel distance to radiation therapy and receipt of radiotherapy following breast-conserving surgery. J Natl Cancer Inst 2000;92: 269–271. 10. Voti L, Richardson LC, Reis IM, et al. Treatment of local breast carcinoma in Florida: The role of the distance to radiation therapy facilities. Cancer 2006;106:201–207. 11. McDonald MW, Godette KD, Butker EK, Davis LW, Johnstone PAS. Long-term outcomes of IMRT for breast cancer: A single institution cohort analysis. Int J Radiat Oncol Biol Phys 2008;72:1031–1040. 12. Pignol J, Olivotto I, Rakovitch E, et al. A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol 2008;26: 2085–2092. 13. Freedman GM, Anderson PR, Li J, et al. Intensity modulated radiation therapy (IMRT) decreases acute skin toxicity for women receiving radiation for breast cancer. Am J Clin Oncol 2006;29: 66–70. 14. Harsolia A, Kestin L, Grills I, et al. Intensity-modulated radiotherapy results in significant decrease in clinical toxicities compared with conventional wedge-based breast radiotherapy. Int J Radiat Oncol Biol Phys 2007;68:1375–1380. 15. Fisher J, Scott C, Stevens R, et al. Randomized phase III study comparing best supportive care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97-13. Int J Radiat Oncol Biol Phys 2000;48: 1307–1310. 16. Donovan E, Bleackley N, Denholm E, et al. Randomized trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol 2007;82:254–264. 17. Hurkmans CW, Cho BCJ, Damen E, Zijp L, Mijnheer BJ. Reduction of cardiac and lung complication probabilities after breast irradiation using conformal radiotherapy with or without intensity modulation. Radiother Oncol 2002;62: 163–171. 18. Bhatnagar AK, Brandner E, Sonnik D, et al. Intensity-modulated radiation therapy (IMRT) reduces the dose to the contralateral breast when compared to conventional tangential fields for primary breast irradiation: Initial report. Cancer J 2004;10: 381–385. 19. Guerrero M, Li XA, Earl MA, Sarfaraz M, Kiggundu E. Simultaneous integrated boost for breast cancer using IMRT: A radiobiological and treatment planning study. Int J Radiat Oncol Biol Phys 2004;59:1513–1522. 20. Singla R, King S, Albuquerque K, Creech S, Dogan N. Simultaneous-integrated boost intensity-modulated radiation therapy (SIB-IMRT) in the treatment of early-stage left-sided breast carcinoma. Med Dosim 2006;31:190–196. 21. 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. 22. Green FL, Page DL, Fleming ID, et al. (eds.) American Joint Committee on Cancer: AJCC cancer staging manual, 6th ed. New York: Springer-Verlag, 2002. 23. Khatcheressian JL, Wolff AC, Smith TJ, et al. American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol 2006;24:5091–5097.
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24. Morrow M, Harris JR. Practice guideline for breast conservation therapy in the management of invasive breast carcinoma. Guidelines and technical standards. American College of Radiology, American College of Surgeons, College of American Pathologists, Society of Surgical Oncology. 2006;543–568. Available at: www.acr.org. Accessed December 19, 2008. 25. Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report 2004. J Clin Oncol 2005;23:619–629. 26. Eifel P, Axelson JA, Costa J, et al. National Institutes of Health Consensus Development Conference Statement: Adjuvant therapy for breast cancer, November 1–3, 2000. J Natl Cancer Inst 2001;93:979–989. 27. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 2005;365:1687–1717. 28. Davis Q, Sutter A, Whitaker D, Johnstone P. Incorporating simultaneous in-field boost (SIB) with inverse-planned IMRT using dynamic multi-leaf collimation (dMLC) to the intact breast after lumpectomy [Abstract]. Int J Radiat Oncol Biol Phys 2004;60(Suppl 1). S277. 29. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:679–694. 30. Guerrero M, Li XA. Analysis of a large number of clinical studies for breast cancer radiotherapy: Estimation of radiobiological parameters for treatment planning. Phys Med Biol 2003;48: 3307–3326. 31. Haustermans K, Fowler J, Geboes K, et al. Relationship between potential doubling time (Tpot), labeling index and duration of DNA synthesis in 60 esophageal and 35 breast tumors: Is it worthwhile to measure Tpot? Radiother Oncol 1998;46: 157–167. 32. National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). August 9, 2006. Available at: http://ctep.cancer.gov/forms/CTCAEv3.pdf, Accessed August 6, 2008. 33. Rose MA, Olivotto I, Cady B, et al. Conservative surgery and radiation therapy for early breast cancer: Long-term cosmetic results. Arch Surg 1989;124:153–157. 34. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 35. DeWyngaert JK, Jozsef G, Mitchell J, et al. Accelerated intensity-modulated radiotherapy to breast in prone position: Dosimetric results. Int J Radiat Oncol Biol Phys 2007;68: 1251–1259. 36. Freedman GM, Anderson PR, Goldstein LR, et al. Four-week course of radiation for breast cancer using hypofractionated intensity modulated radiation therapy with an incorporated boost. Int J Radiat Oncol Biol Phys 2007;68:347–353. 37. van der Laan HP, Dolsma WV, Maduro JH, et al. Three-dimensional conformal simultaneously integrated boost technique for breast-conserving radiotherapy. Int J Radiat Oncol Biol Phys 2007;68:1018–1023. 38. Morganti AG, Cilla S, valentini V, et al. Phase I-II studies on accelerated IMRT in breast carcinoma: technical comparison and acute toxicity in 332 patients. Radiother Oncol 2009;90: 86–92. 39. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006;65: 1–7. 40. Struikmans H, Wa´rla´m-Rodenhuis C, Stam T, et al. Interobserver variability of clinical target volume delineation of glandular breast tissue and of boost volume in tangential breast irradiation. Radiother Oncol 2005;76:293–299.
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41. Li XA, Tai A, Arthur DW, et al. Variability of target and normal structure delineation for breast cancer radiotherapy: An RTOG multi-institutional and multiobserver study. Int J Radiat Oncol Biol Phys 2009;73:944–951. 42. Siebers JV, Keall PJ, Wu Q, et al. Effect of patient setup errors on simultaneously integrated boost head and neck IMRT treatment plans. Int J Radiat Oncol Biol Phys 2005;63:422–433. 43. 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. 44. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardization of Breast Radiotherapy (START) trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomized trial. Lancet Oncol 2008;9:331–341. 45. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardization of Breast Radiotherapy (START) trial B of radiotherapy
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hypofractionation for treatment of early breast cancer: A randomized trial. Lancet 2008;371:1098–1107. 46. Popescu CC, Olivotto I, Patenaude VV, Wai ES, et al. Inverseplanned, dynamic, multi-beam, intensity-modulated radiation therapy (IMRT): A promising technique when target volume is the left breast and internal mammary lymph nodes. Med Dosim 2006;31:283–291. 47. Caudell JJ, De Los Santos JF, Keene KS, et al. A dosimetric comparison of electronic compensation, conventional intensity modulated radiotherapy, and tomotherapy in patients with early-stage carcinoma of the left breast. Int J Radiat Oncol Biol Phys 2007;68:1505–1511. 48. Selvaraj RN, Beriwal S, Pourarian RJ, et al. Clinical implementation of tangential field intensity modulated radiation therapy (IMRT) using sliding window technique and dosimetric comparison with 3D conformal therapy (3DCRT) in breast cancer. Med Dosim 2007;32:299–304.
doi:10.1016/j.ijrobp.2009.05.042
CLINICAL INVESTIGATION
Breast
THREE-YEAR OUTCOMES OF BREAST INTENSITY-MODULATED RADIATION THERAPY WITH SIMULTANEOUS INTEGRATED BOOST MARK W. MCDONALD, M.D., KAREN D. GODETTE, M.D., DAISY J. WHITAKER, C.M.D., LAWRENCE W. DAVIS, M.D., M.B.A., F.A.C.R., AND PETER A. S. JOHNSTONE, M.D., F.A.C.R. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA Purpose: To report our clinical experience using breast intensity-modulated radiation therapy with simultaneous integrated boost (SIB-IMRT). Methods and Materials: Retrospective review identified 354 Stage 0 to III breast cancer patients treated with SIBIMRT after conservative surgery between 2003 and 2006. The most common fractionation (89%) simultaneously delivered 1.8 Gy to the ipsilateral breast tissue and 2.14 Gy to the resection cavity, yielding a breast dose of 45 Gy (25 fractions) and cavity dose 59.92 Gy (28 fractions), biologically equivalent for tumor control to 45 Gy to the breast with sequential 16-Gy boost (33 fractions). Results: A total of 356 breasts in 354 patients were treated: 282 with invasive breast cancer, and 74 with ductal carcinoma in situ (DCIS). For left breast radiation, median cardiac V15 was 2.9% and left ventricular V15 1.7%. Median follow-up was 33 months (range, 4–73 months). Acute toxicity was Grade 1 in 57% of cases, Grade 2 in 43%, and Grade 3 in <1%. For invasive breast cancer, the 3-year overall survival was 97.6% and risk of any locoregional recurrence was 2.8%. For ductal carcinoma in situ, 3-year overall survival was 98% and risk of locoregional recurrence 1.4%. In 142 cases at a minimum of 3 years follow-up, global breast cosmesis was judged by physicians as good or excellent in 96.5% and fair in 3.5%. Conclusions: Breast SIB-IMRT reduced treatment duration by five fractions with a favorable acute toxicity profile and low cardiac dose for left breast treatment. At 3 years, locoregional control was excellent, and initial assessment suggested good or excellent cosmesis in a high percentage of evaluable patients. Ó 2010 Elsevier Inc. Breast cancer, IMRT, Simultaneous integrated boost, Toxicity, Cosmesis.
INTRODUCTION
serving therapy (6, 7). The belief of some referring physicians that the risks of breast RT outweigh the benefits in individual cases appears to be the most common reason for not referring patients for RT (8). Increasing distance to a radiation center is also associated with reduced use of breast RT after BCT, presumably in large part because of the inconvenience of longer commutes for daily treatments during a standard fractionation schedule (9, 10). Refinements in breast RT techniques that are more convenient for patients and promise to minimize acute and late toxicities may result in a greater number of women being appropriately referred for and receiving breast RT. Compared with conventional tangential breast RT, intensity-modulated radiation therapy (IMRT) is a treatment approach that reduces acute skin toxicity, specifically moist desquamation (11–14), the occurrence of which adversely
For both invasive breast cancer (IBC) and ductal carcinoma in situ (DCIS), breast radiation (RT) is an integral component of breast-conserving therapy (BCT) that has shown a local tumor control benefit in several randomized trials and, for IBC, an overall survival benefit in one comprehensive meta-analysis (1). Conventional breast RT is delivered to the whole breast with tangential breast fields, typically over the course of 5 weeks with five daily fractions per week. Total treatment time may extend from 6 to 7 weeks (2), as most women receive an additional radiotherapy boost to the resection cavity to further improve local tumor control, as demonstrated in two randomized studies for IBC (3, 4) and as suggested in a retrospective analysis for DCIS (5). Despite its proven benefit, a substantial minority of patients do not receive breast RT as a component of breast conReprint requests to: Karen D. Godette, M.D., Emory University School of Medicine, Winship Cancer Institute, Department of Radiation Oncology, 1365 Clifton Road NE, Atlanta, GA 30322. Tel: (404) 778-3473; Fax: (404) 778-3670; E-mail: karen@radonc. emory.org Drs. McDonald and Johnstone are currently at the Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN.
Presented in part at the 50th Annual Meeting of the American Society for Radiation Oncology, Boston, Massachusetts, September 21–25, 2008. Conflict of interest: none. Received Jan 24, 2009, and in revised form May 8, 2009. Accepted for publication May 13, 2009.
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affects patient quality of life (12, 15). Early randomized data showed improved late cosmesis with breast IMRT (16), and risk modeling suggested that breast IMRT decreases the probability of late normal tissue complications (17, 18). At Emory University School of Medicine, we began using breast IMRT in 1999, and have previously published our experience with a forward planned technique using dynamic multileaf collimators (DMLC) for tissue compensation (11). In 2003, we transitioned to a multi-beam inverse planned IMRT technique using a simultaneous integrated boost (SIB) to the resection cavity (SIB-IMRT). Although the aim of most breast IMRT techniques is to minimize target inhomogeneities, a breast SIB technique exploits and shapes inhomogeneity to provide differential dosing to the whole breast and the resection cavity. Providing a greater dose per fraction to the resection cavity than to the remainder of the breast allows the traditional sequential boost to be eliminated, thereby shortening the treatment course duration. The radiobiologic implications of breast SIB have been detailed (19) and the dosimetry has been shown to be superior to sequential external beam breast boost techniques (20, 21). This article presents our clinical experience with breast SIB-IMRT, with a focus on acute toxicity, late cosmesis, normal tissue dose, risk of locoregional recurrence (LRR), and overall survival (OS). METHODS AND MATERIALS Patient selection and evaluation Treatment records of The Emory Clinic and Emory University Hospital Midtown were evaluated to identify patients with Stage 0 to III breast cancer receiving breast RT following conservative surgery between January 2003 and December 2006. Patients with distant metastatic disease at presentation, those treated after mastectomy, and male patients were not included. Institutional review board approval was obtained for this analysis. All patients underwent standard staging evaluation after diagnosis and were staged according to the 6th edition of the American Joint Committee on Cancer (22). Patients had routinely scheduled multi-disciplinary follow-up with interval history and physicals and breast imaging according to nationally recognized schedules (23). During the study period, the simultaneous integrated boost technique was our standard institutional treatment approach for intact breast radiotherapy, and no patient or disease characteristics were considered for treatment with this approach. All patients provided written informed consent for treatment, without special consideration of the fractionation schedule employed, as the maximum dose was 2.4 Gy to a portion of the breast, within the range of clinical experience.
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Systemic therapy In accordance with consensus guidelines and available evidence at the time, patients at sufficient risk for distant metastasis were offered adjuvant chemotherapy, whereas those with hormone receptor positive breast cancer generally received adjuvant endocrine therapy with tamoxifen or aromatase inhibitors (23–24). Trastuzumab was usually added for patients with her-2-neu–positive IBC. Preoperative chemotherapy was generally offered to facilitate breast conservation in patients with tumors of a size or in a location that made breast-conserving surgery unlikely without a reduction in tumor size. Sentinel lymph node biopsy and/or axillary nodal dissection was generally performed before initiation of neoadjuvant chemotherapy.
Radiation Radiation therapy was typically initiated within 4 weeks after completion of all surgery and chemotherapy. A computed tomography (CT) scan was obtained for treatment planning in all patients, with 0.25-cm slices from the mid-neck to several centimeters caudal to the breasts. Patients underwent scanning in the supine position with the ipsilateral arm abducted, using a ‘‘T’’ stabilization bar. For larger-breasted women, a slant board was generally used at the discretion of the attending radiation oncologist. At the time of simulation, the physician placed radiopaque wire to encompass all clinically palpable breast tissue and to demarcate the surgical scar to assist in planning the boost. Beginning in 2005, all patients underwent daily localization with kV-kV image matching before treatment.
Definition of treatment volumes We have previously presented our SIB-IMRT technique (28). The ipsilateral whole breast was defined as the breast clinical target volume (CTVbreast), which was contoured by the physician in Eclipse treatment planning software (Varian Medical Systems, Palo Alto, CA) using both the radiopaque wire placed at simulation and adjustments in CT window level. The breast planning target volume (PTVbreast) equaled the CTVbreast with modification of the optimized plan to account for anterior respiratory motion, as described below. The PTVbreast did not include the pectoralis muscles or chest wall, nor the axillary nodal regions, and was auto-cropped to exclude tissue within 3 mm of the outer body contour. The tumor resection cavity was defined as the boost clinical target volume (CTVboost), which was contoured on CT based on postsurgical architectural distortion and surgical clips and was correlated with the surgical scar, operative, and pathology reports. Because the boost prescription isodose typically extended 0.3 to 0.5 cm beyond the CTVboost, the boost planning target volume (PTVboost) was equal to the CTVboost. A boolean operation was then used to subtract the PTVbreast with additional 1 cm margin from the body contour to create a single avoidance structure for plan optimization. The ipsilateral lung was auto-contoured and, for left-sided breast treatment, the cardiac silhouette and/or left ventricle were manually contoured.
Surgery
Treatment planning
Patients underwent conservative surgery with pathologic evaluation according to recognized practice guidelines (24). Re-excision for close or positive margins was performed in accordance with patient and surgeon preferences. Margins were categorized as positive if the pathology report noted the presence of tumor cells at the inked margin of the specimen, close if tumor cells were present within 0.2 cm of the inked margin, and negative if tumor cells were at least 0.2 cm from the inked margin.
Two medial and two lateral nonopposed tangential fields were designed to treat the PTVbreast. The gantry separation between ipsilateral fields ranged from 5 to 10 . Treatment fields were modified to completely avoid the contralateral breast and to minimize the volume of lung tissue in the field. Two additional fields were created to encompass the PTVboost, with field configurations customized to the location of the patient’s resection cavity, generally in a cranio-caudal direction or occasionally with an appositional field.
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After optimization was complete, fluence maps were manually edited to add 2 cm of ‘‘virtual flash’’ anterior to the breast to account for respiratory motion. When a supraclavicular field was prescribed, an anterior half-beam blocked field was matched to the breast IMRT field at the level of the inferior edge of the sternoclavicular junction. This field was treated with 6-MV photons, to a dose of 45 to 50 Gy in 1.8- to 2-Gy fractions, typically prescribed to a depth of 3 to 4 cm. The ipsilateral internal mammary nodes were not electively treated. Most cases (n = 319) were treated with the same SIB fractionation schedule, hereafter termed SIB-A. In this schedule, 25 fractions of 1.8 Gy to PTVbreast (45 Gy total) and 2.14 Gy to PTVboost were given, followed by a dedicated cavity boost of three fractions of 2.14 Gy, bringing the total dose to PTVboost to 59.92 Gy. Two other fractionation schedules were used during the study time period. In SIB-B (n = 25), 28 fractions of 1.8 Gy to PTVbreast (50.4 Gy total), and 2.14 Gy to PTVboost (59.92 Gy total) were delivered simultaneously. In SIB-C (n = 12), 25 fractions of 1.8 Gy to PTVbreast (45 Gy total) and 2.4 Gy to PTVboost (60 Gy total) were delivered simultaneously. The fractionation schedules were used sequentially, independent of patient factors, as we optimized dosimetric parameters.
Radiobiologic rationale To compare SIB-IMRT fractionation with conventional sequential boost schedules, a biologically equivalent dose (BED) was calculated using the linear-quadratic (LQ) model (29): BED ¼ D½1 þ d=ða=bÞgTt =a where D is the total dose, d is the dose per fraction, a and b are LQ parameters, Tt is the total treatment time in days, and g = ln(2)/Tpot, where Tpot is the potential doubling time. The same LQ parameters and Tpot chosen by Guerrero et al. (19) were used, where Tpot = 15 days and a = 0.3 Gy1, as initially derived from clinical data and in vitro measurements (30, 31). In comparison of fractionation schedules for tumor control, an a/b of 10 was used. In comparing schedules for late normal tissue effects, a/b was set at 3 and no treatment time correction was used (29). Table 1 delineates the three SIB fractionation schedules used with comparable sequential schedules. Because SIB-A and SIB-B both gave 28 fractions of 2.14 Gy to the boost volume, the BED for tumor control and late effects are the same and are equivalent to a sequential strategy of 25 fractions of 1.8 Gy to the whole breast followed by eight fractions of 2 Gy to the boost. As previously demonstrated by Guerrero et al. (19), SIB-C was equivalent to 25 fractions of 1.8 Gy to the whole breast followed by 10 fractions of 2 Gy for the boost.
Assessment of toxicity During treatment, acute toxicity was assessed by the physician at on-treatment checks at least weekly. Acute toxicity was retrospectively graded according to the Common Terminology Criteria for
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Adverse Events version 3 (32) based on the highest grade toxicity described in the interval from start of treatment to 4 weeks after completion. Documentation of acute radiation toxicity was the focus of these weekly on-treatment notes, the final treatment summary, and the first follow-up visit, which occurred 1 month after completion of treatment. All these notes were reviewed for descriptions of patientreported symptoms and physical examination findings including skin erythema, dry or moist desquamation, and breast edema. Patient charts were also reviewed for physician assessment of global breast cosmesis, which was graded according to the Harvard criteria, where good or excellent outcomes reflected minimal or no identifiable radiation changes in the treated breast, readily observable significant changes were scored as fair cosmesis, and severe radiation effects reflected a poor cosmetic score (33).
Statistical analysis Follow-up time was calculated from the onset of definitive therapy, either the date of first definitive surgery or the start date of neoadjuvant chemotherapy for those patients treated with preoperative chemotherapy. Only the site of first failure was considered for analysis, using one of the following categories: locoregional recurrence (LRR), contralateral breast tumor recurrence (CBTR), or distant metastasis (DM). The category of LRR included recurrence in the ipsilateral breast, axilla, internal mammary nodes, or ipsilateral supraclavicular space. Overall survival (OS), and risk of LRR, CBTR, and DM were calculated using the method of Kaplan and Meier (34). Patients with synchronous bilateral breast cancer were not scored as having CBTR or included in the number at risk for CBTR, and were included only once in analysis of OS and risk of DM. Statistical analysis was performed using Stata version 9.2 software (StataCorp, College Park, TX).
RESULTS Patient characteristics Between January 2003 and December 2006, 356 breasts were treated in 354 patients: 282 with IBC and 74 with DCIS. Included in analysis were 2 patients with synchronous bilateral breast cancer. Patient characteristics are listed in Table 2. For all patients, the median PTVbreast was 732 cc (range, 80–2931 cc), with a median PTVboost of 23.2 cc (range, 2.6–439 cc). The median ipsilateral lung volume receiving 20 Gy or more (V20) was 10.6% (range, 0–27%). Analyzing left breast cases only (n = 168), the median value for mean heart dose was 2.6 Gy (range, 0.6–7.8 Gy), whereas the median volume of heart receiving 15 Gy or more (V15) was 2.9% (range, 0–17.4%). The median value for the mean left
Table 1. Comparison of fractionation schedules used Schedule name
No.treated
Fractional whole breast
Fractional boost
Nominal total dose
Total no. fractions
SIB-A SIB-B Comparable sequential schedule SIB-C Comparable sequential schedule
319 25 —
1.8 Gy 25 1.8 Gy 28 1.8 Gy 25
2.14 Gy 28 2.14 Gy 28 2 Gy 8
59.92 Gy 59.92 Gy 61 Gy
12 —
1.8 Gy 25 1.8 Gy 25
2.4 Gy 25 2 Gy 10
60 Gy 65 Gy
Abbreviation: BED = biologically equivalent dose.
BED tumor control
BED late effects
28 28 33
67.0 Gy10 67.0 Gy10 65.5 Gy10
102.6 Gy3 102.6 Gy3 98.7 Gy3
25 35
69.5 Gy10 69.4 Gy10
108.0 Gy3 105.4 Gy3
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Table 2. Patient characteristics (Continued)
Table 2. Patient characteristics Patients with IBC (n = 282) Age (y) Median Range Premenopause Postmenopause Breast Right Left Stage I II III Grade 1 2 3 Not reported Estrogen receptor Positive Negative Her-2-neu Positive Negative Unknown Triple negative Margin Negative Close Positive pLNs (+) 0 1–3 $4 Not assessed ENE NA CTX pCR rate Adj CTX Adj HT Fractionation SIB-A SIB-B SIB-C Patients with DCIS (n = 74) Age (y) Median Range Premenopausal Postmenopausal Breast Right Left Tumor size Median Range Grade 1 2 3 Necrosis present Margin Negative Close Positive
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55 24–89 85 (30%) 197 (70%) 152 (54%) 130 (46%) 171 (61%) 96 (34%) 15 (5%) 77 (27%) 100 (35%) 92 (33%) 13 (5%)
Estrogen receptor Positive Negative Not assessed Adj HT Yes No Fractionation SIB-A SIB-B SIB-C
58 (78%) 6 (8%) 10 (14%) 49 (66%) 25 (34%) 68 (92%) 3 (4%) 3 (4%)
Abbreviations: Adj CTX = adjuvant chemotherapy; Adj HT = adjuvant hormonal therapy; DCIS = ductal carcinoma in situ; ENE = extranodal extension in involved lymph nodes; NA CTX = neoadjuvant chemotherapy; not assessed = no lymph node dissection done; pCR rate = pathologic complete response to neoadjuvant chemotherapy; pLNs (+) = number of pathologically involved lymph nodes; SIB = simultaneous integrated boost.
202 (72%) 80 (28%) 55 (20%) 210 (74%) 17 (6%) 60 (21%) 237 (84%) 42 (15%) 3 (1%) 211 (75%) 52 (18%) 10 (4%) 9 (3%) 17/62 (27%) 44 (16%) 11/44 (25%) 104 (37%) 173 (61%) 251 (89%) 22 (8%) 9 (3%) 56 38–85 15 (20%) 59 (80%) 36 (49%) 38 (51%) 0.7 cm 0.1–5 cm 7 (9%) 33 (45%) 34 (46%) 55 (74%) 61 (82%) 10 (14%) 3 (4%) (Continued)
ventricle dose was 2.4 Gy (range, 0.4–14.7 Gy), whereas the median V15 for the left ventricle was 1.7% (range, 0–37.5%). Outcomes Acute toxicity and cosmesis. In 353 of the 356 treated cases (99%), data were available to grade acute toxicity. The acute skin toxicity was Grade 0 in four treated breasts (1%), Grade 1 in 196 (56%), Grade 2 in 152 (43%), and Grade 3 in one (<1%). Three patients (<1%) developed acute breast cellulitis. An assessment of global breast cosmesis at a minimum of 3 years of follow-up was available in 142 cases (40%). Among these, 96.5% were judged as good or excellent, while 3.5% were considered fair, with no patients judged to have a poor cosmetic outcome. Survival, local and distant failure. The median follow-up time for all patients was 33 months (range, 4–73 months). Among the 282 breasts treated for IBC, there were eight ipsilateral breast tumor recurrences, two ipsilateral axillary nodal recurrences, one simultaneous axillary and supraclavicular recurrence, and one ipsilateral supraclavicular recurrence simultaneous with distant metastases. The Kaplan-Meier risk of any LRR at 3 years was 2.9%, with an OS of 97%. There were three CBTR for a 3-year risk of 0.4%. Nine patients had DM as a component of first failure, yielding a 3-year risk of 2.7%. Among the 74 breasts with DCIS, there was one ipsilateral breast recurrence with a Kaplan-Meier risk of any LRR at 3 years of 1.4%, and an OS of 98%. There were no instances of CBTR or DM observed in the patients with DCIS. Analysis of local failures. Among the 8 patients with IBC and IBTR, four were in the same quadrant as the primary, three were in separate quadrants from the original tumor, and one recurrence was a diffuse inflammatory breast cancer. Of the four recurrences in the same quadrant, two were more than 2 cm from the lumpectomy site, whereas two recurred adjacent to the original lumpectomy site in breast tissue receiving 50 to 60 Gy in 1 patient and 57 Gy in the other patient.
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dosimetry in selected patients for those with the expertise to offer this modality. Efforts such as inspiratory breath hold, currently used at our institution, may further reduce cardiac dose in treatment of the left breast. Although breast IMRT can improve target homogeneity and reduce dose to normal structures (17, 18), there remains a theoretical increased risk for secondary malignancies (39). Most breast IMRT techniques, including our own, use tangential field arrangements, which reduce the low-dose spread seen in typical multi-directional IMRT field arrangements for other disease sites. However, breast IMRT still requires more monitor units for delivery with the likelihood of more scatter dose. These concerns deserve our continued careful consideration and require long-term follow-up. Our previous evaluation of 121 patients treated with breast IMRT compensation found a 3% rate of secondary malignancy at 7 years, which was not significantly different from the 4% rate observed in a contemporaneous cohort of patients treated with conventional radiation (11). Detecting a difference in the rate of secondary malignancies with breast IMRT would undoubtedly require a substantially larger sample size and still longer follow-up. One of the challenges of inverse-planned breast IMRT is the interobserver and interinstitutional variability in attempts at delineating CT-based target volumes (40, 41). The recent development of Radiation Therapy Oncology Group (RTOG) consensus guidelines and a contouring atlas for breast radiotherapy planning will hopefully improve homogeneity in target definitions and facilitate comparison between future studies. Our institutional PTVbreast did not include all the tissue encompassed in standard tangential breast fields, as it specifically excluded the pectoralis muscles, chest wall, and the axilla. Because of the geometry of tangential fields used, however, the subpectoral lymph nodes and portions of axillary Level I generally still received significant dose. The three axillary nodal recurrences in our series all occurred in tissue that received essentially the same dose as would have been delivered with standard tangents. Our PTVboost was smaller than described by most institutions for sequential boost techniques, being limited to the resection cavity as identified by CT changes and surgical clips. We used this boost volume definition with an understanding
There was one ipsilateral breast tumor recurrence in a patient with DCIS, which recurred immediately anterior to the lumpectomy site in breast tissue that had received 60 to 63 Gy. Among the 3 patients with IBC and a component of axillary recurrence, 2 experienced recurrence in Level I axillary tissue that had received 46 Gy in 1 patient, and 50.4 Gy in the second, and 1 patient in Level II axillary tissue that had received 50.4 Gy. The 2 patients with failure in the supraclavicular fossa had not received supraclavicular radiation. DISCUSSION Several planning studies have investigated SIB-IMRT (19–21, 35), but published clinical experience with breast SIB is limited. Freedman et al. (36) reported their experience with hypofractionated breast IMRT using a simultaneous electron boost in 75 patients. In their report, the hypofractionated regimen was well tolerated, with acute dermatitis comparable to that observed with standard fractionation regimens, although long-term cosmesis data were not yet available. A three-dimensional conformal breast SIB technique was reported by van der Laan et al. (37), with a favorable acute toxicity profile in the first 90 patients treated. Morganti et al. (38) reported on 201 patients treated with SIB-IMRT, including 102 patients treated with the SIB-C fractionation reported here. The acute toxicity observed with the SIB-C fractionation appeared similar to historical controls, and with a median follow-up time of 24 months, locoregional control was excellent. Our report includes the largest reported series of patients treated with breast SIB, as well as one of the largest numbers of patients treated with breast IMRT. Table 3 lists several recent series of breast IMRT or breast SIB that reported ipsilateral lung doses and heart doses for patients with left-sided disease. Because of differences in individual patient anatomy and differences in target volume definitions and fractionation used, direct comparison between studies would be inappropriate, but the normal tissue doses in our experience appear to be comparable to those achieved in these mostly planning studies. None of these studies included comparison to interstitial breast brachytherapy as a boost modality, which may offer more optimal
Table 3. Select published dosimetry Study (Ref)
No. cases
Boost dose
No. fxs
50
None
25
10 20 10 91
45 50 50.4 40.5
None None 66.4 48
25 25 28 15
1.4-2.3 2.3 5.25 2.0
NR 7.2% 12.5% 1.3%
30 356
50.7 45
64.4 59.92
28 28
4.8 2.6
5.5% 10.6%
Year
Technique
BCCA (46)
2006
IMRT
5
UAB (47) UPMC (48) Loyola (20) NYU (35)
2007 2007 2006 2007
IMRT IMRT SIB-IMRT SIB-IMRT
Netherlands(37) Emory
2007 2009
SIB-3DCRT SIB-IMRT
Breast dose
Mean heart dose 12.8
Ipsilateral lung V20 15.1%
Comment Planning study; IMNs included Planning study Planning study Planning study Prone treatment 51 left side breasts 90 patients treated 168 left-side breasts
Abbreviations: fxs = fractions; IMNs = internal mammary lymph nodes; IMRT = intensity-modulated radiation therapy; NR = not reported; Ref = reference; SIB = simultaneous integrated boost; V20 = volume receiving $20 Gy. All doses are given in Gy.
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that the SIB-IMRT technique provides an intermediate dose range gradient around the boost target whereas the boost prescription isodose itself generally extended in a 0.3- to 0.5-cm halo around the PTVboost. Siebers et al. (42) have evaluated the effect of such ‘‘nesting’’ of dose levels inherent in an SIB-IMRT technique and have shown that target volume coverage in the head and neck is minimally influenced by random patient setup errors of up to 5 mm, although the investigators still recommended use of PTV expansions to ‘‘reduce the effect of setup errors in the overall dose evaluation.’’ Additional consideration was given to the difference in BED with SIB-IMRT. If 60 Gy is considered the minimum cumulative boost dose when using a sequential boost schedule, with SIB-A fractionation, 57.7 Gy provided a biologically equivalent dose for tumor control, so that with SIB-IMRT, a slightly larger volume than the prescription boost isodose received the equivalent of 60 Gy given sequentially, providing an additional safety margin. An analysis of the local recurrences seen in our series identified three recurrences adjacent to the resection site, and two of the three received dose comparable to what would have been delivered with a sequential technique using larger boost margins of 1 to 2 cm. Our method of boost target delineation appears clinically effective with our SIB-IMRT technique, with no apparent increase in local recurrences, although strong consideration should be given to the addition of a PTV expansion to the boost CTV. This study was retrospective, with relatively short followup, and cosmetic evaluation was limited to a physician assessment of global breast cosmesis, scored according to the Harvard criteria, with no available patient assessment or photographic record. Although further follow-up is warranted to better assess the ultimate cosmesis in patients treated with SIB-IMRT, long-term follow-up of the Harvard experience showed that excellent cosmesis scores at 3 years were likely to remain excellent, whereas good scores were more likely to improve than to worsen by 7 years of follow-up (33). The SIB-A fractionation used in the majority of patients treated in our series resulted in a five-fraction reduction in treatment duration compared with a sequential boost strategy. This 1-week reduction in treatment is relatively modest compared with other, more aggressively hypofractionated whole-breast treatment schedules. Randomized trials of whole-breast irradiation using fraction sizes of 2.66 to 3.3
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Gy (43–45) found efficacy comparable to that of traditional fractionation, but the widespread adoption of such hypofractionation in the United States has been limited by persistent concerns about late cosmesis, lack of a boost in some schedules, applicability for patients with larger breast sizes, and the lack of data on late cardiac side effects with these larger fraction sizes. Our SIB-A fractionation schedule offers an alternative approach that offers a 1-week shortening in treatment duration while closely conforming the areas of high dose to the tumor resection cavity so that the majority of the breast tissue receives 1.8 to 2 Gy per fraction and cardiac dose is kept low. Accelerated partial breast irradiation (APBI) offers the most hypofractionated treatment schedule currently available, although whole breast irradiation remains the standard of care pending the results of NSABP B-39 / RTOG 0413. Assuming that the efficacy and cosmetic outcomes of APBI are ultimately found comparable to whole-breast regimens, it is likely that whole-breast radiation will remain the treatment of choice for a subset of women based on resource availability or patient characteristics that preclude APBI as currently envisioned. Whole-breast radiation remains essential in successful breast-conservation therapy, and continued attention should be given to radiation planning and delivery techniques that seek to improve convenience and to minimize both acute and late toxicities. CONCLUSION A breast SIB-IMRT technique was developed that reduced treatment duration by 5 fractions compared with an equivalent sequential boost technique. Retrospective analysis of 356 breasts in 354 patients treated with this SIB-IMRT technique found that it was associated with a favorable acute toxicity profile. For left breast tumors, the cardiac volume receiving high dose was minimal. These results were seen in patients treated without a defined CTV to PTV margin expansion, and SIBIMRT to larger treatment volumes may not be associated with the same dosimetry or toxicity profile. At 3 years, the overall survival and locoregional control were excellent for both invasive disease and DCIS. An initial assessment in 142 patients with a minimum of 3 years of follow-up suggested a good or excellent cosmetic result in a high percentage.
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