Abstract

Purpose: To investigate the inter-observer variability in breast tumor bed delineation using magnetic resonance (MR) compared to computed tomography (CT) at baseline and to quantify the change in tumor bed volume between pre-treatment and end-of-treatment MR for patients undergoing whole breast radiotherapy.

Materials/Methods: Forty-eight patients with breast cancer planned for whole breast radiotherapy underwent CT and MR (T1, T1 fat-suppression (T1fs) and T2) simulation in the supine treatment position prior to radiotherapy, and MR (T1, T1fs and T2) at the end of treatment in the same position. Two observers delineated fifty tumor beds on the CT and all MR sequences and assigned cavity visualisation scores (CVS) to the images. The primary endpoint was inter-observer variability, measured using the conformity index (CI).

Results: The mean CVS at baseline were 3.14 (CT), 3.26 (T1), 3.41 (T1fs) and 3.58 (T2). The mean CI were 0.65, 0.65, 0.72 and 0.68, respectively. T1fs significantly improved inter-observer variability compared to CT, T1 or T2 (p < 0.001, p < 0.001, and p = 0.011, respectively). The CI for T1fs was significantly higher than T1 and T2 at the end of treatment (mean 0.72, 0.64 and 0.66, respectively; p < 0.001). The mean tumor bed volume on the T1fs sequence decreased from 18 cm3 at baseline to 13 cm3 at the end of treatment (p < 0.01).

Conclusions: T1fs reduced inter-observer variability on both pre- and end-of-treatment scans and measured a reduction in tumor bed volume during whole breast radiotherapy. This rapid sequence could be easily used for adaptive boost or partial breast irradiation, especially on MR linear accelerators.

IntroductionMultiple randomised controlled trials have established adjuvant radiotherapy following breast-conserving surgery as standard of care in the management of early-stage breast cancer to reduce the risk of local recurrence (LR).1Liljegren G Holmberg L Bergh J et al.10-Year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial., 2Fisher B Anderson S Bryant J et al.Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer., 3Veronesi U Cascinelli N Mariani L et al.Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. An updated meta-analysis of randomised trials also reported a significant reduction in the risk of breast cancer death at 15 years.4Early Breast Cancer Trialists' Collaborative G Darby S McGale P et al.Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. LR risk is greatest within the region of the tumor bed.5Veronesi U Marubini E Mariani L et al.Radiotherapy after breast-conserving surgery in small breast carcinoma: long-term results of a randomized trial. Accurate delineation of the lumpectomy tumor bed is therefore fundamental to the success of both breast boost and partial breast irradiation (PBI) in preventing LR.6Clarke DH Le MG Sarrazin D et al.Analysis of local-regional relapses in patients with early breast cancers treated by excision and radiotherapy: experience of the Institut Gustave-Roussy., 7van Limbergen E van den Bogaert W van der Schueren E Rijnders A. Tumor excision and radiotherapy as primary treatment of breast cancer. Analysis of patient and treatment parameters and local control., 8Salvadori B Marubini E Miceli R et al.Reoperation for locally recurrent breast cancer in patients previously treated with conservative surgery.While computed tomography (CT) is superior to clinical-based planning in defining the tumor bed volume,9Bates AT Swift CL Kwa W Moravan V Aquino-Parsons C. A computed tomography-based protocol vs conventional clinical mark-up for breast electron boost., 10Hepel JT Evans SB Hiatt JR et al.Planning the breast boost: comparison of three techniques and evolution of tumor bed during treatment., 11Benda RK Yasuda G Sethi A Gabram SG Hinerman RW Mendenhall NP. Breast boost: are we missing the target?. studies have shown variable results in tumor bed delineation between observers, with conformity indices between 0.31 – 0.76.12Landis DM Luo W Song J et al.Variability among breast radiation oncologists in delineation of the postsurgical lumpectomy cavity., 13Li 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., 14Hurkmans C Admiraal M van der Sangen M Dijkmans I. Significance of breast boost volume changes during radiotherapy in relation to current clinical interobserver variations., 15Struikmans H Warlam-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., 16Kosztyla R Olson R Carolan H Balkwill S Moiseenko V Kwan W. Evaluation of dosimetric consequences of seroma contour variability in accelerated partial breast irradiation using a constructed representative seroma contour. Features of the lumpectomy tumor bed on CT associated with lower inter-observer agreement include small volume, low cavity visualisation score, retroareolar location, dense breast parenchyma and close proximity to the pectoralis muscle.12Landis DM Luo W Song J et al.Variability among breast radiation oncologists in delineation of the postsurgical lumpectomy cavity., 13Li 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., 14Hurkmans C Admiraal M van der Sangen M Dijkmans I. Significance of breast boost volume changes during radiotherapy in relation to current clinical interobserver variations., 15Struikmans H Warlam-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.,17Petersen RP Truong PT Kader HA et al.Target volume delineation for partial breast radiotherapy planning: clinical characteristics associated with low interobserver concordance.,18Smitt MC Birdwell RL Goffinet DR. Breast electron boost planning: comparison of CT and US. Surgical clips to delineate the tumor bed has been recommended,19Localising the tumour bed in breast radiotherapy.,20Coles CE Wilson CB Cumming J et al.Titanium clip placement to allow accurate tumour bed localisation following breast conserving surgery: audit on behalf of the IMPORT Trial Management Group. but has not been uniformly adopted in North America, including at our centre.To further improve tumor bed visualisation and inter-observer variability in tumor bed delineation, magnetic resonance (MR) imaging has been compared to CT. Previous investigations comparing the two modalities have yielded wide ranging results however, with some finding no benefit of MR imaging over CT21Giezen M Kouwenhoven E Scholten AN et al.MRI- versus CT-based volume delineation of lumpectomy cavity in supine position in breast-conserving therapy: an exploratory study., 22Mast M Coerkamp E Heijenbrok M et al.Target volume delineation in breast conserving radiotherapy: are co-registered CT and MR images of added value?., 23Kirby AM Yarnold JR Evans PM et al.Tumor bed delineation for partial breast and breast boost radiotherapy planned in the prone position: what does MRI add to X-ray CT localization of titanium clips placed in the excision cavity wall?., 24Pogson EM Delaney GP Ahern V et al.Comparison of Magnetic Resonance Imaging and Computed Tomography for Breast Target Volume Delineation in Prone and Supine Positions. and others finding significant improvements in tumor bed visualisation and conformity indices with the use of MR imaging.25Jolicoeur M Racine ML Trop I et al.Localization of the surgical bed using supine magnetic resonance and computed tomography scan fusion for planification of breast interstitial brachytherapy., 26Huang W Currey A Chen X et al.A Comparison of Lumpectomy Cavity Delineations Between Use of Magnetic Resonance Imaging and Computed Tomography Acquired With Patient in Prone Position for Radiation Therapy Planning of Breast Cancer., 27Al-Hammadi N Caparrotti P Divakar S et al.MRI Reduces Variation of Contouring for Boost Clinical Target Volume in Breast Cancer Patients Without Surgical Clips in the Tumour Bed. Past investigations have used a variety of MR sequences, but conclusions on the ideal sequence are inconsistent and uncertainty still exists.28Ahn KH Hargreaves BA Alley MT et al.MRI guidance for accelerated partial breast irradiation in prone position: imaging protocol design and evaluation.,29Jacobson G Zamba G Betts V Muruganandham M Buechler-Price J. Image-Based Treatment Planning of the Post-Lumpectomy Breast Utilizing CT and 3TMRI.Several studies using serial CT scans have also found that the lumpectomy surgical bed significantly decreases in volume with time from surgery, which can lead to larger volumes of normal breast tissue being irradiated in boost and partial breast treatments.30Yang TJ Elkhuizen PH Minkema D et al.Clinical factors associated with seroma volume reduction in breast-Conserving Therapy for early-stage breast cancer: a multi-institutional analysis., 31Sharma R Spierer M Mutyala S et al.Change in seroma volume during whole-breast radiation therapy., 32Chen X Qiao Q DeVries A et al.Adaptive replanning to account for lumpectomy cavity change in sequential boost after whole-breast irradiation., 33Mohiuddin MM Nichols EM Marter KJ Flannery TW. Decrease of the lumpectomy cavity volume after whole-breast irradiation affects small field boost planning., 34Flannery TW Nichols EM Cheston SB et al.Repeat computed tomography simulation to assess lumpectomy cavity volume during whole-breast irradiation. Adaptive planning may be useful for some patients who have significant reductions in the tumor bed volume over time. To our knowledge, only a single study has used MR imaging to investigate patterns of tumor bed volume change, in the setting of PBI.35Jeon SH Shin KH Park SY et al.Seroma change during magnetic resonance imaging-guided partial breast irradiation and its clinical implications.

The aims of this study were to investigate the inter-observer variability in tumor bed delineation using three MR sequences compared to CT at baseline and to quantify the change in tumor bed volume between pre-treatment and end-of-treatment MR for patients undergoing whole breast radiotherapy.

Methods and Materials PatientsResearch ethics board approval and patient consent was obtained for this study. Between August 2013 and October 2014, forty-eight female patients planned for whole breast radiotherapy after breast-conserving surgery for in situ or early stage invasive breast cancer (Tis, T1-2; N0-1, AJCC 7th edition)36The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. were enrolled in the study. Two patients had bilateral breast cancer. Therefore, a total of fifty lumpectomy tumour beds were included for analysis. All patients were prescribed 42.4 Gy/16 fractions to the breast, except for three 50 Gy/25 fractions. Sequential cavity boost was prescribed to 27 patients for young age (≤ 50) and/or close margin  Imaging

Patients initially underwent planning CT at a median time from surgery of 46 days (range 14 – 187) in the supine position on a MT-350 breast board (CIVCO Medical Solutions, Kalona, Iowa), with the ipsilateral arm raised and abducted. 2mm slices were acquired from mid-neck to below the diaphragm on a Brilliance wide-bore CT Scanner (Brilliance, Philips Medical Systems, Bothell, WA), with in-plane resolution of 1 mm x 1 mm. The clinically palpable breast tissue and surgical lumpectomy scar were outlined with radio-opaque wires.

All patients underwent two sets of MR imaging in the same treatment position, the first prior to breast radiotherapy at a median time from planning CT of 1.9 days (range 0 – 17), and the second in the final week of radiotherapy at a median time from the first MRI of 35 days (range 18 – 67). Imaging was performed on an open bore 3.0-T Verio system (Siemens Medical Systems, Erlangen, Germany) incorporating an 8-channel Spine Matrix coil, with an 8-channel torso coil placed on the chest, with a field-of-view of 400mm, in-plane resolution of 1.3 × 1.3 mm, and slice and gap thicknesses of 3mm and 0.5mm. Three-dimensional (3D), non-contrast axial images were acquired on voluntary inhale breath hold and three sequences were performed at each timepoint: T1 weighted volumetric interpolated breath hold examination (VIBE), T1 fat-suppression (T1fs) spectrally adiabatic inversion recovery (SPAIR) and T2 half-Fourier acquisition single shot fast spin echo (HASTE). The T1 and T1fs sequences were each performed in a single breath hold with a scan time of 19 seconds (s) and a spinal coil bandwidth of 490 Hertz per pixel (repetition time [TR] = 4.19ms, echo time [TE] = 1.47ms, FA = 9 degrees). The T2 sequences were performed in a total scan time of 1 minute and 21s (16s per breath hold), with a bandwidth of 781 Hertz per pixel (TR = 2000ms, TE = 98ms, FA = 150 degrees).

 Lumpectomy tumor bed definition and analysisEach tumor bed was assigned to one of three locations using CT: within fatty glandular breast tissue; within dense glandular breast tissue; against the chest wall musculature. With surgical clips absent in 90% of the tumor beds in our study, identification of tumor bed (or “cavity”) varied across cases. Two observers (a radiation oncologist (XX) and a clinical fellow (XX)) first assigned individual cavity visualisation scores (CVS) to each image set as per the guidelines of Landis et al., where: CVS-1 = cavity not visualised; CVS-2 = cavity visualised but margins indistinct; CVS-3 = cavity visualised with some distinct margins and heterogeneous appearance on CT; CVS-4 = cavity with mild heterogeneity on CT and majority of margins distinct; and CVS-5 = homogenous appearance of the cavity on CT and all margins clearly seen.12Landis DM Luo W Song J et al.Variability among breast radiation oncologists in delineation of the postsurgical lumpectomy cavity. Mean CVS ± standard deviation (SD) were calculated for CT and each MR sequence from the average of the observers’ CVS. Each observer then independently contoured the lumpectomy tumor bed on all CT and MR images, blinded to one another's contours. The inter-observer variability between each paired observers’ contours was assessed by measurement of the conformity index (CI): the ratio of the common volume to the union volume. CI ranges from 0, in which there is no overlap in volume between the observers’ contours, through to 1 which indicates complete concordance. Lumpectomy volumes and statistical analysis

The mean tumor bed volumes ± SD were firstly calculated for each observer's contours on CT and the pre-treatment MR sequences and compared. Then, relationships between tumor bed volume and CVS, and mean tumor bed volume on the pre-treatment and end-of-treatment MR sequences were also evaluated using Pearson correlation coefficients and paired t-test, respectively. CVS, CI, and volumes from the CT and MR images were compared using the repeated-measures analysis of variance (ANOVA) test. When the p value from the ANOVA test was < 0.05, differences were determined using the Tukey post hoc test.

Results

Patient and tumor characteristics are listed in Table 1.

 Lumpectomy tumor bed volumes

The mean ± SD tumor bed volumes at baseline were 18.67 ± 20.13 cm3 for CT, 17.16 ± 17.32 cm3 for T1, 18.13 ± 17.25 cm3 for T1fs, and 17.08 ± 18.18 cm3 for T2 (Table 2). There were no significant differences in mean overall volumes between the MR sequences and CT, with MR:CT volume ratios of 0.92, 0.97 and 0.92 for T1, T1fs and T2 respectively. At the end of whole breast radiotherapy, the mean surgical bed volumes had significantly reduced on each MR sequence in comparison to the baseline MR images (p ≤ 0.0001), with a mean volume reduction of approximately 30% from 18.1 cm3 to 13.0 cm3 for T1fs and 90% of the surgical beds reducing in volume over time. As planning CT was not repeated at the end of treatment, comparisons with MR were not performed at that timepoint.

 Cavity visualisation score

The mean ± SD CVS at baseline were 3.14 ± 1.08 for CT, 3.26 ± 0.99 for T1, 3.41 ± 0.97 for T1fs, and 3.58 ± 1.04 for T2. At the end of treatment, the mean ± SD CVS were 3.15 ± 0.96 for T1, 3.29 ± 0.94 for T1fs and 3.31 ± 1.03 for T2. There were no significant differences between the two observers’ mean CVS. The CVS tended to be higher for larger tumor beds (Pearson's correlation coefficient 0.53). Compared to CT, baseline T1fs and T2 MR sequences significantly improved the CVS (p < 0.01). There were no significant differences in CVS between T1fs and T2. At the end of treatment, there were no significant differences in mean CVS among T1, T1fs and T2 sequences (p = 0.20).

 Tumor bed location

Mean overall CVS and conformity index as a function of tumor bed location are listed in Table 3. Cases in which the tumor bed was surrounded by fatty glandular breast tissue had the greatest mean overall CVS and conformity indices. Tumor beds located within dense glandular breast tissue had the lowest mean overall CVS and conformity indices for CT, T1fs and T2.

 Inter-observer variabilityAt baseline, the mean ± SD conformity indices were 0.65 ± 0.15 for CT, 0.65 ± 0.14 for T1, 0.72 ± 0.15 for T1fs and 0.68 ± 0.15 for T2. T1fs significantly improved inter-observer variability compared to CT, T1 or T2 (ppp = 0.011, respectively). A representative case of tumor bed delineation by the two observers is demonstrated in Figure 1. At the end of treatment, the mean ± SD conformity indices were 0.64 ± 0.12 for T1, 0.72 ± 0.12 for T1fs and 0.66 ± 0.12 for T2. Inter-observer variability was significantly improved with T1fs compared with T1 or T2 (ppp = 0.001 and p = 0.038, respectively). For tumor beds with a mean CVS ≥ 4 on CT, baseline T1fs alone significantly improved the mean conformity index compared with CT, from 0.76 to 0.80 (p

Figure 1A representative case of tumor bed delineation by observers 1 (blue) and 2 (red) on CT, T1-weighted, T1 fat-suppression (T1fs) and T2-weighted MRI.

Discussion

This study investigated the inter-observer variability in breast tumor bed delineation using 3 MR sequences (T1, T1fs, T2) compared to CT at baseline and quantified the change in tumor bed volume between pre-treatment and end-of-treatment MR for patients undergoing whole breast radiotherapy. T1fs reduced inter-observer variability on both pre- and end-of-treatment scans and measured a reduction in tumor bed volume during whole breast radiotherapy.

Appropriate treatment of the breast tumor bed for both boost and accelerated partial breast irradiation relies on accurate delineation of the tumor bed, without which local control could be compromised or unnecessary normal tissue exposed. While it is established that CT is more accurate in defining tumor bed volumes than clinical mark-up alone, studies still show considerable variation exists between radiation oncologists when contouring tumor beds.9Bates AT Swift CL Kwa W Moravan V Aquino-Parsons C. A computed tomography-based protocol vs conventional clinical mark-up for breast electron boost., 10Hepel JT Evans SB Hiatt JR et al.Planning the breast boost: comparison of three techniques and evolution of tumor bed during treatment., 11Benda RK Yasuda G Sethi A Gabram SG Hinerman RW Mendenhall NP. Breast boost: are we missing the target?., 12Landis DM Luo W Song J et al.Variability among breast radiation oncologists in delineation of the postsurgical lumpectomy cavity., 13Li 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., 14Hurkmans C Admiraal M van der Sangen M Dijkmans I. Significance of breast boost volume changes during radiotherapy in relation to current clinical interobserver variations., 15Struikmans H Warlam-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., 16Kosztyla R Olson R Carolan H Balkwill S Moiseenko V Kwan W. Evaluation of dosimetric consequences of seroma contour variability in accelerated partial breast irradiation using a constructed representative seroma contour. The use of MRI in breast radiotherapy has so far yielded variable results, but there is significant heterogeneity in the methods of the publications to date, with many studying small number of patients.In our study, T1fs and T2 MRI were found to improve CVS when compared with CT. Giezen et al. found no overall benefit of T1 MRI over CT in 15 patients with surgical clips, and moreover at low CVS found that CT achieved better CI than MRI, suggesting that surgical clips were important for better visualisation of tumor beds on CT for low CVS.21Giezen M Kouwenhoven E Scholten AN et al.MRI- versus CT-based volume delineation of lumpectomy cavity in supine position in breast-conserving therapy: an exploratory study. While some studies have identified seroma extension beyond clips, and inconsistencies remain a problem at many centres with the number and location of clip placements (if placed at all), consistent placement of surgical clips can be helpful for accurate delineation of the tumor bed.19Localising the tumour bed in breast radiotherapy.,20Coles CE Wilson CB Cumming J et al.Titanium clip placement to allow accurate tumour bed localisation following breast conserving surgery: audit on behalf of the IMPORT Trial Management Group.,37Yang Z Chen J Hu W et al.Planning the breast boost: how accurately do surgical clips represent the CT seroma?.,38Goldberg H