MRI reduces variation of contouring for boost clinical target volume in breast cancer patients without surgical clips in the tumour bed

There are two clinical scenarios in which delineation of the lumpectomy cavity (LC) is required during breast cancer radiotherapy: boost after whole breast irradiation (WBI) and accelerated partial breast irradiation (APBI). WBI after organsparing surgery reduces the risk of breast cancer recurrence and mortality.1,2 Delivery of boost dose to the LC clinical target volume (CTV_LC) is an important component of this treatment. It has been shown to improve local control at an increased risk of moderate to severe fibrosis.3 APBI is becoming increasingly utilized in selected groups of patients. Shorter overall treatment time, reduced radiation exposure of the organs at risk and comparable disease control make it a good alternative to WBI for early stage disease.4-6 High accuracy of contouring and precision of treatment delivery are needed to optimize the delicate therapeutic ratio between treatment benefit and side effects. This is especially important in the setting of highly conformal dose delivery to a small volume, such as boost after WBI and becomes critical during APBI where the entire dose is delivered to the CTV_LC. Inter-observer variation (IOV) in contouring is one of the main contributors to the cumulative budget of uncertainties in radiotherapy.7 It may undermine the gain of high-precision technologies, blur the dose-effect relations and compromise treatment comparisons. For the individual patient, geographical miss of the target volume leads to increased chance of relapse, while unnecessary irradiation of normal tissues increases the probability of side effects. Respecting the common contouring guidelines accompanied by adequate training and high quality imaging are the most important strategies to reduce contouring variation.7-11

Currently, CT is the standard imaging modality for CTV_LC contouring. Due to its poor ability for soft tissue depiction, placement of surgical clips or markers at the edges of LC is recommended to improve tumour bed delineation.12-16 But reliability of inserted markers as a surrogate for tumour bed is a matter of debate9,16-18 and omission of their placement in some patients poses a special challenge to the radiation oncologist during CTV_LC delineation.19 The role of MRI for contouring in breast cancer radiotherapy is controversial11,20-23 and the evidence to support its use in patients without markers in the tumour bed is scarce.24,25 In our present study, we aimed to (1) quantify the IOV and (2) assess the accuracy of CT- and MRI-based CTV_LC contouring in patients without clips in the LC. Our null hypothesis was that there is no statistically significant difference between MRI- and CT- based contouring in this supgroup of patients.

Results of the present study rejected our null hypothesis: MRI, when compared with CT, led to (1) reduced IOV and (2) improved accuracy for CTV_LC contouring in patients without markers in the tumour bed. Keeping in mind the cost and complexity of utilizing MRI for radiotherapy planning, our findings justify its use in selected cases.

CT-based delineation of the LC is prone to IOV, even among experienced radiation oncologists.7,10,11,31-34 In various tumour sites, MRI has been shown to reduce contouring uncertainties when compared with CT.35-41 Based on these findings, MRI is becoming increasingly implemented for contouring and is the recommended gold standard in some malignancies.42 However, there are many studies that failed to demonstrate improved contouring with the use of MRI for various tumour sites.43-47 As far as breast cancer is concerned, several authors investigated the impact of adding MRI to CT for delineation of lumpectomy cavity with negative or inconclusive outcome.11,16,20-23 Den Hartogh et al. found that addition of postoperative MRI to CT guided delineation marginally increased the target volumes and failed to reduce the IOV.22 Similarly, Kirby et al. reported that addition of MRI to CT resulted in tumour bed volumes that were discordant with those based on CT and clips alone. With the use of MRI, the tumour bed volume increased in 28 out of 30 cases included, resulting in a median CTV increase of 10.3% (−33.6%−80.9%).20 Mast et al. compared CT- and MRI-based delineations of breast and LC by four observers in 10 patients. The mean CI for the LC was 0.52 for CT and 0.48 for CT combined with MRI (p = 0.33).23 In another similar study, the inter-observer agreement was even lower. While MRI and CT enabled similar visualization of the LC, MRI resulted in lower generalized CI (0.32 +/− 0.25) when compared with CT (0.52 +/− 0.21).21

The rationale to use MRI in our study was to improve contouring consistency for cases without surgical clips in the tumour bed. Mean CVS on MRI (3.88 +/− 0.99) was significantly superior to CVS on CT (3.05 +/− 1.07) (p = 0.001). CVS was improved in 92% and was accompanied by an increase of CI and AI in 83% cases. For both modalities, we found an increase of CI_gen and AI with increasing CVS (Figure 2). Therefore, inter-observer concordance depended directly on the ability to visualize lumpectomy cavity, which was superior on MRI. Of note, in all of the reports which failed to show benefit of MRI, clips were placed at the edges of LC.11,16,20-23 In a study by Giezen et al., four observers (2 radiologists and 2 radiation oncologists) obtained a mean CVS of 2.8 +/− 1.7 for MRI and 2.9 +/− 1.7 for CT. In contrast to our findings, Giezen et al. demonstrated superiority of CT over MRI for contouring, especially at low CVS.21 With increasing CVS values, both modalities performed better and the CI_gen from MRI approached that from CT. The lack of added value of MRI in this and other published studies20-23 could be attributed to better visibility of the clips on CT, introducing a bias in its favour, as acknowledged by the authors.21 This effect becomes especially important at low CVS values. Our positive findings could be attributed also to the fact that MRI was performed as simulation procedure, replicating the CT planning supine position as much as achievable.

To our knowledge, there are only two publications in addition to our present study which demonstrated added value of MRI for delineation of post-lumpectomy tumour bed.24,25 In the study by Jolicoeur et al., there were no surgical clips implanted at time of lumpectomy. Three observers delineated the post-lumpectomy tumour bed in 70 patients. Highly significant IOV was demonstrated for CT based contouring of the tumour bed (p < 0.0001), while agreement was high for the MRI-based approach. The volumes of MRI based contours were 30–40% smaller than the CT-derived volumes. In another study with three observers and 36 cases, mean CVS for the LC was 3.3 and 4.3 for CT and T2 MRI, respectively (p < 0.0001). Better CVS was reflected in superior inter-observer consistency and volumetric agreement of contours. The authors stated that surgical clips were occasionally, but not routinely placed by the referring surgeons.24

Based on our results, addition of MRI to CT could be justified as a good alternative to CT alone for selected patients in whom the placement of surgical clips in the tumour bed was omitted. But despite concerns regarding their reliability as a surrogate for tumour bed17,18,48, placement of clips followed by CT-based contouring of LC should be currently considered as the gold standard.16 This approach has been shown to improve the accuracy of LC contouring, reduce the overall boost volume and help prevent geographical miss and underdosage of the LC.13-16,49-52 But the technique of placement and the number of inserted markers differs between institutions and surgeons and is even omitted in some cases. Kirwan et al. recently reported on a retrospective study of 196 cases, assessing the compliance with recommendations for clip insertion. Although recommended by the clinical guidelines, the clip insertion was omitted in 56% of cases while additional 7% of patients had only two or fewer clips inserted. Ten of 31 referring surgeons routinely omitted clips and the omission rate was significantly higher for centres with low (≤ 1 patient) when compared with high (≥ 14 patients) rate of recruitment to IMRT clinical trials (67% vs. 27%, respectively; p < 0.001).19 These results emphasize the need for good collaboration between radiation oncologists and surgeons and standardization of clip placement.9 Auditing of clip insertion has been suggested as one of the key performance indicators for quality control of breast cancer surgery.19

Based on their study which demonstrated reduction of IOV when adding MRI to CT, Jolicoeur et al. proposed that the use of CT-MRI fusion may obviate the need for surgical clips altogether.25 However, while reduction of IOV indicates increased contouring agreement, it doesn’t necessarily imply improved accuracy. To assess the accuracy, individual delineations would in theory need to be compared with the ground truth or correct delineation. In the absence of the histopathological proof, the ground truth is an elusive concept. Different approaches, including simultaneous truth and performance level estimation (STAPLE), expert consensus (EC) or their combination have been used as surrogates for correct delineation.27,53 In our current study, the concept of EC delineation was applied. Keeping in mind the limitations of the “ground truth” definition, our results indicate that adding MRI to CT improves contouring accuracy in cases without surgical clips in the LC cavity.

Comparison of our results with findings of other studies is challenging due to the variable conditions under which contouring was performed and the diversity of methods used for IOV assessment. The impact of variables such as experience and specialty of observers, use of guidelines, type of surgery, etc. should be kept in mind when comparing reports.16 As far as the methods for IOV assessment are concerned, CI is one of the most commonly used quantifiers. In general, CI is a measure of overlap between analyzed volumes, but there is a diversity of formalisms used in the literature which cannot be directly compared. The generalized CI (CI_gen) formalism is independent of the number of delineations, enabling the comparisons between studies with different number of observers.29 Regardless of the CI formalism used, the impact of contouring variation on CI is inversely proportional to the size of the analyzed volume. Therefore, same absolute deviation between analyzed contours will result in lower CI for small volumes (i.e. tumour bed) when compared with larger volumes (i.e. tumour bed with a margin). The effect of margins on CI is particularly relevant in breast cancer, where the contours are typically cropped to exclude the skin and chest wall, improving the apparent conformity between observers.

In our study, mean CI_gen of 0.67 (+/− 0.12) and 0.74 (+/− 0.07) was obtained for CT and MRI-based contouring of CTV_LC, respectively. Major et al. studied the impact of contouring guidelines on consistency of LC and planning target volume (PTV) contouring for multi-catheter partial breast irradiation. When contouring was performed on pre-implant scans by experienced observers and according to the guidelines (similar conditions as in our study), they obtained a CI_gen of 0.59 and 0.73 for LC and PTV, respectively. The margins for PTV were similar to our margins for CTV_LC, making the resulting volume sizes comparable between the two studies. Of note, CI_gen for PTV, obtained by CT and clip-based contouring54 was similar to our CI_gen for CTV_LC, obtained by MRI in patients without clips. The lower CI_gen for LC when compared with PTV⁵⁴ reflects the sensitivity of CI_gen to the volume size, as described above. Majority of other published studies reported on contouring uncertainties for tumour bed, with a CI_gen ranging from 0.32–0.52.21-23 Our results compare favourably with the existent literature. This can be attributed to strict compliance with contouring guidelines, participation of experienced observers and use of high quality imaging.

Low number of observers and cases that were entered in analysis can be considered as the main limitations of our study. Considering the need for specific expertise in breast radiotherapy, experience in interpretation of MRI and relative rarity of cases without clips in LC, higher number of observers and cases is challenging to obtain outside a multi-institutional setting. This challenge is reflected in the limited number of observers and cases in studies, published by several authors before us.20-23 Multi-centre collaborative projects may represent the optimal approach to overcome this limitation and shed more light on the subject of contouring uncertainties in general.

In breast cancer patients without clips in the tumour bed after breast conserving surgery, MRI improved the visualization of lumpectomy cavity when compared with CT. Consequently, interobserver agreement and accuracy of contouring of lumpectomy cavity clinical target volume were improved. Placement of surgical clips, followed by CT-based contouring is the gold standard for contouring of the boost volume for postoperative irradiation in breast cancer. However, in patients without clips, addition of MRI to CT simulator images should be considered to improve delineation accuracy. Further studies with higher number of observers and cases are required to confirm our findings.

The study protocol was reviewed and given ethical approval by the Institutional Medical Corporation Medical Research Centre. Datasets generated and analysed during study are not publicly available due to patient confidentiality but are available from corresponding author on reasonable request and after institutional approval. This study was not funded.