Post- versus intra-operative implant for breast cancer interstitial brachytherapy: How to choose?

Surgical consideration of breast conserving surgery technique for multi-catheter breast implant

Candidates for MIB primarily target those with small tumors undergoing BCS. APBI with POB ensures excellent oncologic outcomes and cosmetic results [21].

Long-term cosmesis relies heavily on surgical criteria and technique, regardless of radiation technique used. Essential surgical criteria, involving minimal specimen size and discreet incisions (periareolar, axillary, sub-mammary, or lateral chest) to avoid volume depletion or poor cosmesis, are recommended to achieve the optimal cosmesis outcomes [28]. This “scarless” surgery allows a wide subcutaneous dissection over a tumor location and local reconstruction with adjacent breast tissue, which is a very suitable surgical technique for MIB. Unlike other intra-operative radiation techniques, such as intra-operative electron radiotherapy technique (IOERT), MIB adapts to incisions, avoiding extensive scars. Additionally, oncoplastic surgical techniques are not a contraindication for MIB [29]. Whenever the tumor target area is easily identified by breast surgeon and radiation oncologist, together, they can delineate the correct area to implant.

Intra-operative sentinel node biopsy, conducted through the same incision, minimizes scarring [30] and provides crucial information for APBI patients, especially in case of IOB MIB technique. Furthermore, intra-operative pathology analysis of margin status addresses the need for further breast tissue resection [31]. The resection margin measurement, in different directions, determine the surgical cavity to be covered by implant. Precise surgical clip placement is also crucial for accurate target definition. If no clips are inserted in place, the area to be targeted cannot be easily and securely identified, and this can contribute to inaccurate target volume delineation [4, 32, 33]. In conclusion, an efficient collaboration between the radiation oncologist and breast surgeon is essential for MIB success.

General aspects of multi-catheter interstitial breast brachytherapy

Regardless of clinical indication, MIB prioritizes optimal coverage of tumor bed and clinical target volume (CTV). The implant procedure begins with a “guide needle” at the tumor bed center, with subsequent needles encircling it on planes to ensure complete coverage. A breast template facilitates parallel and geometric catheter placement, while a template-free or free-hand techniques demand expertise [25]. Adhering to Paris system, catheters are positioned at a parallel distance of 1.2 cm to 1.6 cm across distinct planes. This ensures a uniform dose distribution, minimizes high-dose regions, and facilitates a sharp dose fall-off beyond the irradiated zone to protect organs at risk (OARs) [34, 35]. After implant completion, metallic needles are replaced with plastic catheters (Figure 1D). Single-plane implants are generally discouraged to prevent dose inhomogeneity. Pre-operatively measured distances exceeding 10 mm between the tumor and skin prevent skin hyperpigmentation. Special consideration is crucial for deep implants near the chest wall to mitigate risks of neuropathy or costal fractures.

Fig. 1

A case of post-operative brachytherapy (POB) with pre-implant requirements, implant procedure, and dosimetry planning issues. A) Pre-POB CT. The open cavity due to seroma and clips are shown

Fig. 1

Cont. B) Implant design of implant direction based on scar. C) X-ray-guided POB procedure. Verification of surgical clips (white circle) and first needle location with MIB template. Metallic vectors are located around surgical clips based on template. D) Metallic vectors are replaced by plastic tubes. E) CT planning with CTV, clips, OARs delineation, catheter reconstruction, and isodose distribution

Post-operative multi-catheter breast brachytherapy

Post-operative brachytherapy is performed post-BCS as a separate surgical procedure, after fulfillment of clinical criteria. Technical and clinical aspects are summarized in Table 1, with an illustrative example shown in Figure 1.

Organizational aspect

Post-operative brachytherapy should be ideally conducted within 12 weeks after BCS, or at most, 4 weeks after the completion of adjuvant chemotherapy. Non-radiotherapy hospitals are encouraged to facilitate patient referral to specialized breast brachytherapy centers. Figure 2 shows the workflow of organizational process for POB.

Fig. 2

Post-operative brachytherapy (POB) and intra-operative brachytherapy (IOB) flowchart of organizational procedures

Intra-operative multi-catheter breast brachytherapy

After tumor and sentinel node removal, IOB takes place concurrently with BCS, requiring coordinated efforts of radiation oncologists, breast surgeons, and pathologists. Technical and clinical details are outlined in Table 1, with an illustrative example in Figure 3.

Fig. 3

A case of intra-operative brachytherapy (IOB) with pre-implant requirements, implant procedure, and dosimetry planning issues. A) Breast MRI and breast ultrasound, with measures of tumor-skin distance

Fig. 3

Cont. B) Pathology macroscopic visualization, margin measurement, and tumor location. C) Intra-operative design of implant procedure of a patient with a peri-areolar incision. Topographical identification of a high-risk area of tumor bed in surgical cavity (solid white line), with clip references (white arrows). The area to be implanted corresponds to a tumor bed plus a 1-2 cm margin, based on visualization of breast specimen and tumor location with margin relationship. D) Final breast conserving surgery with IOB. E) CT planning with CTV, clips, OARs delineation, catheter reconstruction, and isodose distribution

General aspects of planning and treatment delivery

Historically, brachytherapy dose prescriptions relied on reference points, and 2D dose distribution planning was guided by catheter geometries. Modern practice follows 3D image-guided brachytherapy as the gold standard. It incorporates CT images for delineation, planning, and dose calculation. Inverse dose planning and DVH evaluation enhance dose distribution conformity, accuracy, reproducibility, and quality for MIB [34]. Post-implant CT scan validation ensures the accuracy of catheter insertions and implant geometry. The 3D image-guided brachytherapy planning begins with reconstructing catheters and delineating CTV and organs at risk [4] (Figures 1E and 2E).

For CTV delineation, the GEC-ESTRO guidelines determined the process for POB [32, 33]. For IOB, the contour of CTV corresponds to the catheter-based area implanted [39]. Surgeon collaboration can verify clip position. In both the MIB techniques, additional post-implantation needles may enhance coverage.

Second, the prescription dose must cover 90% of CTV, assuring a proper dose homogeneity index (DHI) value. Physicists and radiation oncologists optimize dose delivery for a homogenous dose distribution, following guidelines [4].

Thirdly, once the plan is ready, the treatment begins with implant connection to afterloading machine, typically with high-dose-rate (HDR) sources, such as iridium-192, although PDR can also be used. This procedure takes a few minutes and is repeated 1 to 10 times, depending on the prescribed schedule, at intervals of at least 6 hours. Hospitalization is generally unnecessary. Antibiotic prophylaxis is at the physician discretion, and particularly recommended in IOB. Different protocols can be considered, adapted to each hospital or healthcare system’s patient workflow.

POB vs. IOB: Technical and dosimetry considerations

Post-operative brachytherapy and IOB share comparable technical aspects, but nuanced differences deserve emphasis regarding target volume accuracy, number of catheters used, and CTV volume delineation. The real-time nature of IOB provides certainty in target identification accuracy [25, 39]. Moreover, IOB series report a lower number of inserted catheters, covering the tumor bed, pioneering the concept of minimally invasive tumor bed implants [38]. In terms of target delineation, POB is based on cavity type (opened or closed) [29, 30], adhering to the published guidelines for consistent criteria. For IOB, a secure CTV delineation approach is the catheter-based methodology advocated by Sato et al. [39]. This has resulted in smaller irradiated volumes in IOB series, reporting median CTV volumes of approximately 30-44 cc, equivalent to 4-5% of breast tissue irradiation [15, 17, 40]. This contrasts with a 81 cc of CTV (range, 7-275 cc) in the GEC-ESTRO phase III trial [3], or a 63 cc (range, 27-120 cc) in the Budapest trial [41] using POB. Additionally, patients with small breasts, where single-plane implantation is mandatory and CTV is therefore reduced, were not recognized as a risk factor for ipsilateral breast tumor recurrence (IBTR), with a 4-year IBTR-free survival of 97.5% [42]. CTV volumes and OARs doses significantly surpass those observed in other radiation techniques, such as IMRT-APBI or CyberKnife [43-45].

While a dosimetric analysis comparing CTV volumes and other dosimetry parameters between POB and IOB has not yet been published, early-term clinical and toxicity outcomes do not reveal substantial and obvious differences. A recent multi-center study reported initial analysis showing that POB and IOB provide equivalent dosimetric and early-term clinical (oncological and toxicity) results, presented at the ASTRO 2023 meeting [19]. See Table 2 and the examples provided in Figures 1 and 3.

POB vs. IOB: Clinical outcome considerations

Pivotal phase III APBI trials, including the Budapest, GEC-ESTRO, and NSABP B-39/ RTOG 0413 trials, have comprehensively validated MIB for APBI. These trials primarily focused on the POB approach, highlighting its safety and efficacy with more than a decade of case follow-up [21, 41, 46]. In contrast, IOB was explored in institutional prospective registered phase I-II studies with shorter follow-ups [24-27, 47].

The Budapest trial reported a 10-year local recurrence (LR) rate of 5.9%, a 10-year disease-free survival (DFS) of 85%, and a 10-year overall survival (OS) of 80% [20]. The GEC-ESTRO group showed a 10-year loco-regional recurrence (LRR) rate of 3.51%, a 10-year DFS of 84.89%, and a 10-year OS of 90.47% [21]. The RTOG 0413 trial revealed a 10-year LC rate of 3.9%, a 10-year DFS of 78.1%, and a 10-year OS of 90.6% for patients undergoing POB [46]. Turning to APBI-IOB, Sato et al. reported an IBTRs-FS rate of 98.9% in 237 patients treated after 50 months, along with a remarkable 4-year OS and DFS of 99.6% [47]. Cambeiro et al. observed a 100% LC rate for 88 patients, with a median follow-up of 38.4 months [25]. Hannoun-Lévi et al. demonstrated the safety of the technique with 26 elderly patients, showing a 5-year LRFS rate of 100% and a 88.5% OS at a 5-year follow-up [26]. Oncological outcomes from IOB studies are presented in Table 2. While the number of patients treated with IOB-APBI is small and long-term oncological outcomes are still pending, no visible differences in oncological outcomes emerge when comparing IOB with POB. Preliminary results from a recent multi-center study presented at the 2023 ASTRO meeting, involving 516 APBI-eligible patients treated with IOB (50.2%) or POB (49.8%), revealed a 4-year cumulative incidence of local and regional recurrence rate of 2% and 1%, respectively, with no statistically significant differences based on the implant procedure [19]. Additional details are provided in Table 2.

POB vs. IOB: Safety and toxicity considerations

The safety of each technique is assessed through complication rates during implantation. POB complications highlighted in the trials are negligible, and may not be exhaustively reported. The GEC-ESTRO trial reported a 5% rate of infection or low-grade breast injury, but up to 20% rate of mild grade 1 hematoma compared with 2.2% in the WBRT arm [48]. In the RTOG 95-17 study, the following infrequent complications were reported: 1 pneumothorax, 12 infections, 1 wound dehiscence, and 1 case of bleeding in 99 patients treated with POB [46]. Notably, Polgar et al.’s extended experience revealed minimal and not clinically relevant early complications for POB [49, 50]. In case of IOB, a rate of around 10% of peri-operative complications was reported, with common issues, including minor bleeding, infection, and wound healing. Hannoun-Lévi et al. reported a 9% complication rate [17], while Cambeiro et al. documented 11.3% complications, including limited hemorrhages, wound healing, seroma, and infection [25]. Additionally, due to limited data availability, complications related to the IOB procedure may sometimes be attributed to post-lumpectomy problems. In conclusion, both the techniques exhibit comparable surgical and treatment-related safety, with no notable differences in complication rates and toxicities. Further details can be compared in Table 2.

POB vs. IOB: Patient considerations

Patient considerations for POB vs. IOB highlight potential advantages and nuances. For older patients, particularly sensitive to the impact of anesthesia on cognitive functions, IOB stands out by avoiding a second anesthesia procedure [24, 51]. However, local anesthesia in POB could be a viable alternative for such cases. Quality of life (QOL) outcomes, when comparing multi-catheter brachytherapy APBI (POB and IOB) with standard WBRT, favors the brachytherapy approach [52-54]. On one hand, IOB’s efficient process within a single-hospital minimizes logistical complexities [55]; yet, on the other hand, POB offers patients flexibility to choose a different radiotherapy center or physician. The choice between IOB and POB may also depend on institutional factors, country regulations, and healthcare system preferences, impacting whether breast brachytherapy patients are treated as in-patients or out-patients. While specific hospitalization is not mandatory, post-procedure care protocols may vary based on institutional norms.

POB vs. IOB: Surgeon considerations

Independent of the technique used (POB or IOB), the implant design is normally adapted by the radiation oncologist to the surgeon’s lumpectomy technique and choice of incision. The surgical approach for IOB may vary from a perpendicular to a periareolar incision aligned with tumor location. Contemporary trends favor oncoplastic procedures that preserve cosmetic outcomes. Notably, the choice of surgical technique does not contraindicate either IOB or POB, as long as implant geometry is assured. Gimeno-Morales et al. [15] demonstrated the compatibility of minimal invasion surgery with IOB, underlining a crucial collaboration between surgeons and brachytherapists to achieve optimal cosmetic results. Evidence supporting POB feasibility with oncoplastic surgery was provided by Roth et al. [29]. To enhance cosmetics and minimize complications, a Japanese study proposed incision relocation to an inconspicuous site, mitigating wound healing issues in peri-operative APBI irradiation [56].

POB vs. IOB: Radiation oncologist considerations

Logistics play a pivotal role in the choice of breast brachytherapy. Figure 2 provides an outline of both the techniques. IOB presents notable advantages by expediting the local treatment process. Standard APBI schedules include 34 Gy in 10 fractions or 32 Gy in 8 fractions, while very accelerated partial breast (vAPBI) schedules further trim treatment duration to 1 or 2 days (18 Gy/1 fx., 16 Gy/1 fx., 6.2 Gy/4 fx., or 7.5 Gy/3 fx.) [15, 16, 26, 57]. Such a reduction supports patient compliance, lowering infection and implant discomfort risks.

Currently, extreme hypofractionation with 5 fractions WBRT [58] is very competitive with MIB vAPBI schedule treatments [15, 16, 26, 57], because no special equipment for brachytherapy is required. Even though breast brachytherapy alleviates long waiting lists, granting patients swifter irradiation access, with potential economic benefits to healthcare systems, this is not well-described in the literature.

A significant disadvantage of IOB to highlight is the number of patients deemed ineligible for APBI post-implantation after receiving definitive pathology results. This ranges around 15-27% [25, 42, 59, 60]. Nonetheless, these patients who have already undergone IOB can receive an anticipated boost, followed by WBRT [25, 38] or catheter explantation. In contrast, POB allows a simple reconsideration of the appropriate adjuvant irradiation technique if the final pathology makes APBI unsuitable. Fortunately, in these cases, the patient would not receive brachytherapy procedure. Further information are presented in Figure 2 and Table 3.