A comparative study based on deformable image registration of the target volumes for external-beam partial breast irradiation defined using preoperative prone magnetic resonance imaging and postoperative prone computed tomography imaging

Breast-conserving therapy (BCT), which involves a wide local excision followed by radiotherapy to the whole breast, has become the standard treatment for early-stage breast cancer [1]. However, for patients with a low risk of recurrence, accelerated partial breast irradiation (APBI) is now gaining acceptance as an alternative to whole breast irradiation (WBI) for early-stage cancer [2‐6]. In addition, external-beam partial breast irradiation (EB-PBI) is an important approach to APBI. Polgar et al. [2] have reported that the efficacy of EB-PBI is equivalent to that of WBI. However, there are conflicting data regarding the acute and late toxicity of APBI. An Italian randomized trial has indicated [7] that the rates of Grades 1 and 2 acute skin toxicity in a APBI cohort were remarkably lower than those in a WBI group with decreases of 17 and 18.2%, respectively. However, in a prospective trial of 2135 patients from Canada [8], poor cosmesis at 3 years was significantly increased among those treated with APBI compared with WBI treatment, with 29% vs 17% as determined by trained nurses and 26% vs 18% as determined by the patients. Meanwhile, the rates of Grades 1 and 2 toxicity in the EB-PBI patients were also significantly higher than those in the WBI group.

Hence, based on these results, researchers are rethinking all aspects of postoperative EB-PBI. A potential factor that explains the increase in toxicity observed in the APBI group is the irradiation of a larger volume of breast tissue in those patients with poor cosmesis. Whether to ensure therapeutic efficacy or to reduce toxicity and side effects, an essential prerequisite for APBI is the accurate delineation of the target volume. However, defining the target in postoperative EB-PBI varies widely depending on the specimen volume, seroma size, clarity, surgical clips, simulation image, inter-observer variability [9] and other aspects. In addition, there is a volumetric difference for EB-PBI between the prone and supine positions [10]. Moreover, preoperative EB-PBI might be an effective approach to reducing the target volume compared to that in postoperative EB-PBI. It has been reported that both the gross tumor volume (GTV) and planning target volume (PTV) are significantly smaller in preoperative EB-PBI than in postoperative EB-PBI [11, 12].

Preoperative image-guided techniques have been considered effective tools for improving the detection of tumors [13], and due to its high spatial resolution, preoperative magnetic resonance imaging (MRI) has the advantages of detecting occult tumors and providing additional valuable information regarding the primary tumor [14, 15]. At present, there are few reports that focus on the feasibility of preoperative prone diagnostic MRI in guiding postoperative target delineation for prone EB-PBI. Therefore, the aim of this study was to provide a reference for how to use preoperative diagnostic MRI to guide the delineation of postoperative EB-PBI in the prone position.

APBI, as a possible alternative to WBI, offers less overall treatment time and the delivery of a reduced dose to uninvolved portions of the breast and adjacent organs at risk [20, 21]. Undoubtedly, the irradiation of normal breast tissue would be decreased by reducing the EB-PBI target volume, which provides conditions for reducing toxicity or other side effects and improving the cosmetic outcome [22]. During the EB-PBI target definition, first and foremost is the identification and contouring of the GTV. MRI is recognized as an excellent imaging tool in diagnosing a primary breast tumor and has shown the ability to identify mammographically occult carcinoma [14, 15]. In the preoperative APBI study of van der Leij et al. [11], a virtual plan was made for preoperative EB-PBI, which resulted in a reduction in the GTV compared to that with postoperative EB-PBI. Hence, we aimed to clarify whether the delineation of the target volumes for postoperative prone EB-PBI might benefit from preoperative prone diagnostic MRI and to provide a reference for how to use preoperative diagnostic MRI to guide the delineation of target volumes for postoperative EB-PBI in the prone position.

Based on our analysis, the results showed that the GTV_postCT was significantly larger than the GTV_preMR by 12.58 cm³. Van der Leij et al. [11] also confirmed that a statistically significant difference was evident between the preoperative GTV and the postoperative tumor bed (7.71 cc lower in the preoperative EB-PBI target volume). In addition, our study demonstrated that the CTV_{preMR + 10} and PTV_{preMR + 15} were significantly smaller than the CTV_{postCT + 10} and PTV_{postCT + 15}, respectively. Compared to the CTV_{postCT + 10} and PTV_{postCT + 15}, the CTV_{preMR + 20} and PTV_{preMR + 25} were significantly greater by 51.81 cm³ and 43.99 cm³, respectively. Hence, if the expanded margin was too large, the preoperative EB-PBI would lose the advantage of reducing the dose to the ipsilateral breast, and the main factor to consider for the margin extension is the subclinical range. Controversy exists regarding EB-PBI treatment in terms of the subclinical range. Faverly et al. [23] have shown that a 10-mm tumor-free margin gives the best positive predictive value for breast cancers of limited extent. At present, a lumpectomy is performed with an intended macroscopic margin of at least 1.0 cm [24], and this value also represented a subclinical range that had been covered by previous studies [25, 26]. Therefore, it is resonable to reconstruct the CTV_MRI by adding a 1.0-cm margin around the GTV_MRI. However, Schmitz et al. [13] indicated that typical treatment margins of 10 mm around the GTV_MRI might include occult disease in 52% of patients for MRI-guided BCT. When expanded with a 20-mm margin around the GTV_MRI, a subclinical lesion could also be found in one-fourth of the patients. This might have been a consideration for van der Leij et al. [27] in delineating the CTV_MRI and PTV_MRI by expanding around the GTV_MRI with 20-mm and 25-mm margins, respectively. But, based on our result, the CTV_{preMR + 20} and PTV_{preMR + 25} were significantly greater, so the CTV_MRI and PTV_MRI by expanding around the GTV_MRI with 20-mm and 25-mm margins should not be advised. In our study, in comparison with the CTV_{postCT + 10} based on the postoperative TB, the CTV_MRI was not expanded by 15 mm around the GTV_preMR; however, van der Leij et al.¹¹ have shown that the difference was not statistically significant.

In theory, when there is equilateral excision around the primary tumor, there would be no significant difference between the CTV_{preMR + 10} and CTV_{postCT + 10}, which are defined by expansion from the primary tumor based on preoperative MRI and by the postoperative TB, respectively. This seemingly contradictory difference can be explained by the asymmetric resection of the primary tumors [28]. If the anisotropic surgical margin caused by asymmetrical resection is taken into account, the volumes of the CTV_pre and CTV_post are comparable [11]. Furthermore, Zhang AP et al. [28] and den Hartogh et al. [29] indicated that because the majority of surgeons subjectively perform BCS based on palpation of the boundaries, which results in the asymmetric resection of primary tumors, neither the resection specimen volume nor the TB correlate with the visible tumor volume based on preoperative MRI. However, in our study, the Spearman rank correlation demonstrated that a statistically significant positive correlation exists between the GTV_preMR and GTV_postCT and between the CTV_{preMR + 10} and GTV_postCT. This finding might be explained by the fact that in addition to the determination of the resection range based on palpation, the preoperative imaging data, such as MRI scans, have recently played an increasingly significant role in BCS, and the anisotropy between the specimen edge and tumor edge has been reduced.

MRI is not only the basis for the implementation of preoperative EB-PBI but also helpful for selecting patients suitable for postoperative EB-PBI, guiding postoperative target delineation for EB-PBI [30, 31]. The preoperative diagnostic MRI image was obtained in the prone treatment position, which is the same position as that of prone EB-PBI after BCS. Theoretically, DIR between the preoperative diagnostic MRI and postoperative prone CT simulation images should be conducive to the determination of the targets for postoperative prone EB-PBI. However, our study concluded that when based on the DIR of the thorax, the CI, DI and DSC were all poor for both the GTV_preMR-GTV_postCT and CTV_{preMR + 10}-GTV_postCT comparisons. The distances between the COMs of the GTV_preMR-GTV_postCT and GTV_{preMR + 10}-GTV_postCT were 2.71 cm and 2.67 cm, respectively. Moreover, the breast spatial matching between preoperative diagnostic MRI and postoperative CT simulation was not ideal, showing that the CI, DI and DSC values for the CTV_Breast-MRI-CTV_Breast-CT did not reach 1, for perfect agreement between volumes.

The poor breast spatial matching might be mainly caused by the difference between the dedicated MRI bilateral breast coil and the dedicated treatment board for prone CT simulation. For preoperative diagnostic MRI, there are two apertures open on all sides to allow the bilateral breasts to hang freely away from the chest wall; however, the postoperative CT treatment board only contains an open aperture on one side, whereby only the ipsilateral breast can move away from the chest wall due to gravity in the prone position. Meanwhile, the contralateral breast is pulled away from the ipsilateral side by the baffle as much as possible, which might affect the natural overhang of the ipsilateral breast. Our results indicated that there was relatively poor spatial overlap between both the GTV_preMR and GTV_postCT and between the CTV_{preMR + 10} and GTV_postCT. This result may be attributable to the poor breast spatial matching and could also be the result of the same spatial morphology among the GTV_preMR, CTV_{preMR + 10} and GTV_postCT after DIR. Furthermore, from our analysis that was based on the DIR of the center-coincidence of the GTV_preMR and GTV_postCT, the CI, DI and DSC values for the GTV_preMR-GTV_postCT and the CTV_{preMR + 10}-GTV_postCT were significantly improved compared with those based on the DIR of the thorax; however, these values were still poor. Therefore, it is unreasonable to use preoperative prone diagnostic MRI images to guide the postoperative target delineation for EB-PBI.

Overall, in Chinese early-stage breast cancer patients enrolled to undergo prone EB-PBI, when defining the target based on the preoperative prone MRI images, the target volumes were significantly smaller when compared to those based on postoperative prone CT images. However, a statistically significant positive correlation was found between the MRI- and CT-based target volumes. Although based on DIR, there was relatively poor spatial overlap between the preoperative prone diagnostic MRI images and the postoperative prone CT simulation images for both the whole breast and the target volumes. Hence, it is unreasonable to use preoperative prone diagnostic MRI to guide postoperative target fusion delineation for EB-PBI. In fact, it is feasible to optimize the delineation of the postoperative EB-PBI target volumes by other means, such as clipping the surgical cavity by the surgical team in the presence of the radiation oncologist responsible for contouring for PBI and using respiratory gating with daily on board image verification before delivery of treatment can help in reducing the PTV margins. Further, studies on patterns of failure and adverse cosmetic outcome after EB-PBI can aid in refining the delineation techniques.