One important advance in accelerated partial breast irradiation (APBI) has been the evolution of the external beam radiation therapy (EBRT) technique from basic 3-dimensional (3D) techniques such as mini-tangents or noncoplanar multibeam planning to highly conformal techniques such as intensity-modulated radiotherapy (IMRT) and even stereotactic body radiation therapy (SBRT). These APBI techniques differ in their capacity to deliver the prescribed tumoricidal dose with an appropriate dose distribution to the entire anatomically defined target volume,1 and these recent technological improvements in EBRT have facilitated improved conformality of isodoses around the target volume. The importance of conformality has been highlighted in studies suggesting that low, intermediate, and high doses of radiation to nearby healthy tissue of the ipsilateral breast correlate with inferior cosmetic outcomes.2,3 Several quantitative factors are utilized to objectively evaluate and compare treatment plans; notably, this important element of quality control is not achievable for partial breast irradiation (PBI) utilizing intraoperative radiation therapy methods. As an example, Leonard et al3 reported the effect of dose-volume parameters on cosmetic outcomes from 80 patients treated with 3D-conformal radiotherapy (CRT) APBI and demonstrated that several metrics (eg, V50 and V80, ie, normal breast volumes receiving 50% and 80% of prescription doses) were significantly associated with subcutaneous fibrosis, fat necrosis, worse cosmesis, and higher than grade 2 toxicity. In earlier reports of PBI using EBRT, V50 of the uninvolved breast was limited to 50% of the prescribed dose, ranging from 42% to 49% of the ipsilateral breast in studies utilizing 3D-CRT,3–5 which is much greater than those from brachytherapy studies.6 Notably, the V50 of the uninvolved breast is significantly decreased with advanced techniques such as IMRT and SBRT. In a recent prospective trial of 5 fractions of SBRT-based PBI in an adjuvant setting, the ipsilateral breast V50 was limited to <40% of the prescribed dose, but it was reported to be 24% in 30 Gy in 5 fraction cohort.7 From a different perspective, the ability to permit a steep dose gradient with highly conformal dose delivery can be used to investigate the efficacy of dose-escalated PBI.8

In another consideration, several studies have demonstrated a correlation between incidental radiation dose to heart/lung and major coronary events/second lung cancer.9 In this context, a growing number of breast cancer patients are treated with various techniques or approaches, for heart and lung sparing. When combined with modern high precision in planning and delivery, APBI, which targets smaller volumes, can now effectively avoid low doses to the heart and lung relative to whole breast irradiation, thereby preventing long-term risks of ischemic heart disease and lung cancer.10 Khan and colleagues reported the results of a dosimetric comparison of balloon-based brachytherapy, 3D-CRT, and IMRT. The mean ipsilateral lung V30 and heart V5 were the lowest in the IMRT methods when compared with others.6 As opposed to other APBI techniques, this ability is probably a result of technological improvements that heart, lung, and coronary arteries are delineated on computed tomography (CT)-based images, and the dose delivered to these organs can thus be constrained and optimized using inverse planning.

As the conformality of APBI improves, the accuracy and reproducibility of tumor bed delineation become even more critical. Paradoxically this time-consuming step is probably most susceptible to interphysician variations and human error.11 Studies have shown significant inter and intraobserver variation in consistently defining tumor bed volumes, with the mean conformity index (the sum of the intersections of all possible volume pairs/sum of their unions) ranging from 0.5 to 0.6.11 Therefore, over the last few decades, attention has focused on improving tumor bed volume delineation.12,13 These strategies include using standardized guidelines, surgical clips or fiducial markers, preoperative imaging, and additional postoperative imaging modalities beyond CT scans.

First, postoperative seroma and surgical clips are commonly utilized to define the tumor bed. Kirova et al14 studied the relationship between the gross tumor volume defined on the preoperative images and clips with a 5 mm margin on the postoperative scan in 22 patients: the accuracy of tumor bed delineation was improved if 3 or more clips were placed during the lumpectomy. Atrchian et al15 found that the consistency of tumor bed delineation was significantly improved in the craniocaudal dimension by the presence of surgical clips. Postoperative seroma in the lumpectomy cavity and clear visualization of the seroma on CT images reduces interobserver variation although the presence of seroma could increase the average tumor bed volume. Several studies have investigated the added value of magnetic resonance imaging (MRI) in terms of consistency. Kirby et al16 compared tumor bed volumes delineated using postoperative MRI in the prone position plus CT and surgical clips with those delineated using CT and clips. Addition of MRI to CT allowed to identify additional seroma, hemorrhage, and edema, thus could potentially be useful in the absence of surgical clips. Jolicoeur et al17 evaluated the feasibility of postoperative MRI in the supine position for tumor bed delineation using the prospective cohort. Addition of breast MRI improved interobserver variability by providing a more precise definition of the tumor bed. However, in a study of 10 patients by Mast et al,18 addition of MRI did not improve the interobserver consistency.

Preoperative imaging has also recently been explored as a means to more accurately delineate tumor bed volume.19 A recent study looked at the interobserver consistency of gross tumor volume’s that were contoured on preoperative CT and MRI scans for 12 patients.20 Patients were imaged using either contrast-enhanced CT or MRI in the supine treatment position before undergoing breast-conserving surgery. While interobserver consistency was high for both CT and MRI, the conformality index (volume of agreement among observers/total encompassing volume) was significantly higher for those patients who underwent MRI. Furthermore, after appropriate expansions, the CTV volume was found to be significantly higher on MRI compared with CT (59 cm3 vs 48 cm3).

The use of additional imaging modalities has likewise been examined in an effort to more accurately identify tumor bed volume. One such imaging modality is positron emission tomography-CT (PET-CT). Initial diagnostic PET-CT in the supine position was examined to determine the feasibility of use in localizing tumor bed volume in 25 patients.21 Subsequent to the PET-CT, the patients underwent breast-conserving surgery with the placement of surgical clips. Deformable image registration was then used to fuse the PET-CT with the treatment-planning CT. Two separate volumes were then contoured, 1 based on the surgical clips with a margin of 1 cm and a second based on the 90% maximum standardized uptake value according to the PET-CT registration. The spatial relationship of the 2 volumes was then compared using the distance between the center points of the 2 volumes (Dcenter) and the percent volume of the PET-CT volume that was included in the volume based on the surgical clips (Vin). Although the Dcenter was found to be somewhat discordant at a mean of 1.4 cm, the mean Vin was 94.8%, with 18 of the 25 patients having a Vin of 100%, indicating initial diagnostic PET-CT with deformable registration could feasibly be used to localize tumor bed volume.

Another imaging modality that has recently been reported on is ultrasound. Ultrasound can be utilized at the time of simulation to identify the seroma and subsequently can be used for image guidance. Ultrasound offers the advantages of being nonionizing and providing good image quality in breast tissue. A recent study assessed operator dependence and seroma shifts in image-guided therapy that relied upon ultrasound guidance.22 This study included 15 patients with seromas that were visible on CT scans and that were eligible for randomized PBI studies. Immediately after the CT simulation, the patients had an initial 3D ultrasound performed. The patients then returned 14 to 21 days later, and a second CT scan was performed followed by 3 additional sequential 3D-ultrasounds performed by 3 different technicians. Five contours were created from each of the subsequent ultrasounds performed by 5 radiation therapists. The treatment shifts calculated based on ultrasound guidance did not differ significantly from calculated shifts based on CT guidance. In addition, shifts did not differ significantly between multiple scan acquisitions or between operators on the same scan. However, there was found to be a statistically significant difference in intraoperator variability in seroma shift determination.

Many proposed methods seem to reduce interobserver variation in tumor bed definition, but each has drawbacks.23 The proposed delineating guidelines are intended to be adopted by physicians based on their own interpretation and discretion. Consequently, tumor bed contouring, a very sophisticated operation, is still primarily dependent on the radiation oncologist’s skill.11 In addition, defining a tumor bed using surgical clips or multimodal imaging as surrogates may not always properly reflect the actual tumor bed.

In standard techniques, reproducibility and precision of patient and tumor position are typically obtained through appropriate positioning and 2-dimensional imaging verification. Above and beyond this basic set-up workflow, 3D image-based verification with kV cone beam CT before APBI can further increase the precision and accuracy of EBRT-based ABPI, typically with a match to soft tissue changes suggestive of the lumpectomy volume, or to fiducials such as clips. However, even if the tumor bed is accurately defined, there is still the possibility that its location, shape, and volume will vary dramatically during radiation therapy. Chen et al24 showed that the change in tumor bed volume ranged from a 70% decrease to a 50% increase between the planning CT and the start of RT. The interval between lumpectomy and radiation treatment delivery represents an interval, during which time the initial tumor location can change with respect to the surrogate markers placed at the time of lumpectomy. A study involving 34 breast cancer patients published recently represented the first study to utilize onboard imaging to measure the distance between surgically placed fiducial markers as a measure of seroma size and variability.25 In this study, patients had gold fiducial markers implanted in the seroma cavity at the time of lumpectomy. At the conclusion of the study, it was found that the average intermarker distance (AiMD) was reduced by 19.1% from the start of the simulation to the completion of treatment. In addition, the AiMD was reduced by 10.8% in the time interval between the simulation and the beginning of treatment. The authors determined that the decrease in AiMD fit an exponential function and were able to compute a half-life of 15 days for seroma shrinkage. Jeon et al26 analyzed the MRI data obtained from 37 patients who underwent MRI-guided online adaptive PBI. The mean seroma volume decreased to 60%, 48%, and 40% at the first, sixth, and tenth fractions from 100% at simulation, suggesting that adaptive radiotherapy replanning could be helpful.

Finally, 1 consideration is to record and account for 3D pathologic margins with anisotropic margin expansion of the clinical target volume from the tumor bed to reduce the volume of irradiated volume or to reduce the overall margin due to increased precision of the technology; however, this too can increase the risk of interobserver variation or target misses.27 The position of the tumor bed can change in a subset of patients (eg, larger breast volume) during the course of treatment (ie, in distinction to changes in the volume of the cavity discussed above).28 In 2015, Glide-Hurst et al29 assessed changes in the lumpectomy cavity during external beam radiation treatment (intrafraction variability) using deformable registration. In this study, 16 left-sided and 1 bilateral breast cancer cases were simulated using both a free-breathing CT as well as a 10-phase 4DCT. The results of the analysis showed that for the entire study population, the lumpectomy cavity movement ranged anywhere from 0.8 mm to 3.8 mm with an average of 2.5 mm. In addition, the PTV volumes that were generated using the free-breathing CT were significantly larger than those generated from the 4DCT by an average of 51.5%. Hoekstra and colleagues attempted to evaluate intrafraction motion of the lumpectomy cavity during APBI on a Cyberknife with fiducial tracking. The results of the analysis showed that 0.3 mm to 0.6 mm margins were required for breathing and the margin for drift increased with treatment time: 1.0 mm margin for ≤8 minutes and 2.5 mm margin for ≤32 minutes of total fraction duration. The authors concluded that breathing motion has a limited effect.30

The use of oncoplastic breast surgery has expanded recently. In some cases, large amounts of breast tissue (>25%) are removed then major tissue manipulation is done for breast restoration. As a result, the tumor bed can be shifted quite far from its original location, rendering tumor bed delineation even more challenging. Riina et al31 assessed interobserver variability in the tumor bed delineation in 39 patients who underwent oncoplastic breast surgery. In their study, the use of surgical clips improved interobserver variability, particularly when 4 clips were utilized. However, another recent study by Aldosary et al32 raised questions about the validity of using surgical clips in oncoplastic breast surgery for tumor bed delineation. On realistic breast phantoms, various oncoplastic breast surgery procedures were simulated. Significant clip displacement occurred outside of the original breast quadrant, implying that the best practices on the delivery of APBI for complex oncoplastic breast surgery situations are likely to remain challenging and in evolution.

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