Five Fraction External Beam Partial Breast Irradiation: A User’s Guide

Mature follow-up from multiple randomized phase III trials demonstrated that external beam partial breast irradiation (PBI) is a safe and effective alternative to whole breast irradiation (WBI) for appropriately selected patients with early stage breast cancer.1–5 Acute and late toxicity are significantly less than after WBI with acute grade 1 and 2 toxicity limited to 19.1% and 2%, respectively, and only 4.5% grade 1 late toxicity.1 Despite evidence supporting the safety and efficacy of external beam PBI and the feasibility of delivery in centers around the world, it still remains underutilized. One possible explanation for the slow adoption is the unfamiliarity of radiation oncologists with this treatment. In this user guide we outline patient selection and workflow to aid in implementation of patient-centered, evidence-based external beam PBI.

PATIENT SELECTION

Several suitability criteria have been published for the selection of patients for PBI.5–7 The most recent and inclusive selection criteria comes from the American Brachytherapy Society (ABS) using the most recent trial results (Table 1).8 Alternatively, one can consider utilizing the inclusion criteria of patients on the aforementioned randomized trials.

TABLE 1 - American Brachytherapy Society Partial Breast Irradiation Consensus Criteria8 Suitable Age ≥45 y* Histology and margin Invasive carcinoma with no tumor on ink Ductal carcinoma in situ with ≥2 mm margin Size ≤3 cm Estrogen receptor Any HER2 receptor Negative Positive AND receiving HER2 therapy Extensive lymphovascular space invasion Not present Nodal status Negative

*Patients below 45 years can be considered for PBI if grade 1 to 2 and luminal A.

Margin status is an important issue when considering PBI for a given patient, as the original trials evaluating PBI required a range of margins from no tumor on ink to 5 mm. In today’s landscape with high-quality margin assessment as well as increasing use of shave margins, it has been found that the benefit of wide margins, especially in patients receiving radiation, is very limited.9 We therefore support PBI for patients with invasive disease and negative margins as assessed by no tumor on ink. For patients with DCIS the preferred margin is ≥2 mm, however for a patient otherwise meeting criteria with negative but <2 mm margin, PBI can be considered after adequate counseling.

Some patients who are candidates for PBI may also be recommended adjuvant chemotherapy or immunotherapy. Because of the effectiveness of systemic therapy, in the most recent guideline, PBI can be considered for patients with triple negative or HER2 enriched breast cancer.10 PBI can be delivered in the standard postoperative period before chemotherapy, or can be delayed until after chemotherapy, though cavity delineation may be more challenging, thus warranting transition to WBI.

Another aspect to take into consideration when selecting patients for PBI is the use of oncoplastic surgery, which includes a variety of techniques. The most common oncoplastic technique used with lumpectomy is volume displacement, which includes closing the lumpectomy defect with redistribution of the remaining breast tissue.11 Volume displacement can improve postoperative esthetics; however, some procedures may drastically alter the lumpectomy cavity. More extensive interventions may result in an incision that is not directly over the lumpectomy cavity, margin tissue may not be adjacent to the cavity, clips may not be a surrogate for excision edges, and seroma formation is less likely to occur. The combination of these factors makes targeting of the tumor bed unpredictable and therefore, PBI should be approached cautiously for patients undergoing oncoplastic surgery. If extensive tissue redistribution has occurred, WBI should be offered.

Ideally, surgical clips should be placed at time of lumpectomy to aid in tumor bed delineation. If surgical clips are not placed, the patient should be counseled that if a tumor cavity seroma is not easily delineated at the time of simulation, then WBI should be recommended. For these patients, we recommend computed tomography (CT) simulation soon after lumpectomy to increase the likelihood of tumor bed visualization.

TECHNIQUE

Interstitial brachytherapy has the longest follow-up results of all techniques used for the delivery of PBI.12–14 Other brachytherapy techniques with acceptable oncologic and cosmetic results are balloon-based brachytherapy and seed implants.15–17 Numbers of patients treated with these techniques are declining, because of their invasiveness and the specific training and equipment needed. The results of intraoperative PBI using electrons or low-energy photons are less favorable and are not recommended outside of prospective studies at this time given increased rates of recurrence.18,19 External beam PBI is an attractive alternative as it is noninvasive, widely available and has excellent results. Both static IMRT and volumetric arc therapy are commonly used. It has been shown that the use of a noncoplanar beam-setup can result in lower doses to heart and lung, potentially lowering long-term toxicity.20 Excellent results have also been published for robotic stereotactic radiotherapy and proton PBI, with reduced heart and lung doses.21–23 It is important to balance the additional resources required for these advanced techniques with the gain in long-term toxicity.

DOSE AND FRACTIONATION

At the inception of external beam PBI, treatment was delivered through 3D conformal radiotherapy with twice-a-day fractionation, mirroring brachytherapy treatment delivery.2–4,24,25 As IMRT was introduced, treatment was delivered daily for moderately hypofractionated regimens (10 fractions) and on a nonconsecutive daily basis for ultrahypofractionated regimens (5 fractions).1 With the updated Florence experience, in addition to smaller institutional experiences and the results of the FAST-Forward WBI trial, PBI can be safely delivered over 5 consecutive days without increased toxicity.26,27 Given the long-term outcomes, patient convenience, and ease of administration, we recommend daily fractionation over BID for external beam PBI. The most extensive evidence is for 30 Gy in 5 fractions for PBI.1,28,29 The FAST-Forward WBI fractionation of 26 Gy in 5 fractions is increasingly used in Europe for PBI, although there is no direct clinical evidence for its use in PBI.5,30 Results of the ACCEL trial, which utilized 27 Gy in 5 fractions PBI, are currently limited to toxicity outcomes as the data for oncologic outcomes are still maturing.31 It is important to relate the prescribed dose to the clinical target volume (CTV) margins used. Using a larger margin but a lower dose results in a similar dose distribution as a smaller margin with a higher dose.

In the near future, the number of fractions for PBI may decrease even further, as early results of trials of 1 to 3 fraction PBI, given either preoperatively or postoperatively, show low toxicity rates.32,33

SIMULATION

CT simulation should take place 3 to 5 weeks postoperatively to optimize visualization of the lumpectomy cavity. Patients are most commonly treated in the supine position, however, prone PBI is also feasible for facilities with the necessary immobilization device and experience.26 For patients treated in the supine position, both arms are ideally positioned overhead, using immobilization similar to WBI. The scar is demarcated using a radiopaque wire to aid in cavity delineation. Scan parameters and procedures are equal to those used for WBI. PBI administration without skin marks has been reported,34 however, unless this is standard institutional practice we recommend skin markings to aid in isocenter localization.

Respiratory motion management can be considered, especially for targets in close proximity to the heart. PBI trials utilized free breathing treatment and this remains an acceptable option, however in an effort to decrease organ-at-risk (OAR) dose, patients can be treated with respiratory control. Options range from the simplest form of deep-inspiration breath hold to more complex forms utilizing tracking-and-trailing or breath hold devices.29

If a patient is found to have a large seroma, >5 cm in size or >1/3 of the breast, one should consider seroma aspiration. If the seroma is aspirated, repeat simulation should take place a minimum of 1 to 2 days later to allow for the expected re-accumulation of fluid.

CONTOURING

At the heart of PBI is the ability to accurately delineate the tumor bed, often described as the surgical cavity and representative clips on simulation CT. There should be a 0.5 to 1.0 cm CTV expansion.29 In addition to the simulation CT, physicians should also utilize pre-operative physical exam, imaging, operative report, and pathology report to guide detailed contouring. On the basis of oncologic definitions, the authors agree that the CTV should be cropped to respect natural boundaries, most specifically it should not extend into the chest wall or pectoralis muscle. The CTV should be cropped 3 to 5 mm inside skin surface.

The planning target volume (PTV) expansion is dictated by motion management and reproducibility and should be defined per institution. Commonly, a 0.5 to 1.0 cm PTV margin is used. In recent studies evaluating intrafraction lumpectomy cavity motion, cavity displacement was <0.5 cm, and even less with respiratory motion management, demonstrating that a 0.5 cm PTV margin or even less is reasonable with respiratory motion management.35,36 The PTV should be cropped 3 to 5 mm inside skin to create a PTV_eval for dose volume histogram analysis. Overall, the CTV plus PTV expansion result in a 1.5 to 2.0 cm target expansion on the tumor bed and clips.

OARs that must be contoured for PBI planning include the ipsilateral breast, contralateral breast, heart, lungs, and spinal cord. For use in PBI, the breast contour should exclude the chest wall and pectoralis muscle.

TREATMENT PLANNING

Modern external beam PBI was first implemented using 3D conformal radiotherapy techniques using 4 to 6 noncoplanar beams.24,25 With technological advances, planning transitioned to step and shoot IMRT and is now commonly performed with volumetric arc therapy and sometimes with stereotactic radiotherapy. For many patients, treatment planning and delivery can be achieved with two to three coplanar partial arcs. In addition to target volume coverage, arc angles are optimized to reduce dose to the contralateral breast. For cases in which normal tissue constraints are not being met, such as contralateral breast dose, noncoplanar beams may help achieve planning constraints. Typically plans are designed using 6 MV beams. Flattening filter free beams can be used to decrease the treatment administration time. Isocenter is placed in the lumpectomy cavity, however, it may need to be moved to ensure gantry clearance during arc delivery and cone beam CT.

Commonly used PTV coverage calculated for the PTV_eval include D95% ≥98% with an acceptable alternative of ≥95%. Bolus should not be used and as mentioned previously, the PTV_eval should be cropped inside the skin. The plan should be homogeneous with Dmax preferably ≤105% and certainly ≤110%. Plans with slightly higher hot spots tend to occur when arc angles are limited by the contralateral breast for medial targets. Most recent treatment planning constraints for normal tissue are provided by Marrazzo et al27 and listed in Table 2. Attention should also be given to limit dose in skin and thoracic wall.

TABLE 2 - Florence Trial Normal Tissue Constraints27 Ideal Acceptable Ipsilateral breast—PTV V15 Gy ≤50% V15 Gy ≤60% Contralateral breast Dmax ≤1 Gy Dmax ≤2-3 Gy Heart V3 Gy ≤10% Ipsilateral lung V10 Gy ≤20% Contralateral lung V5 Gy ≤10%

PTV indicates planning target volume.

Uninvolved ipsilateral breast constraints are important to consider, however for patients with a larger PTV or smaller breast, we know from the FAST-Forward trial that 26 Gy in 5 fractions is safe for the whole breast.30 Similarly, based on PTV location or anatomy, a higher contralateral breast dose may be necessary. We do not recommend PBI be abandoned solely based on inability to achieve these OAR constraints, as PBI is very likely still achieving lower OAR doses when compared with the WBI alternative.

IMAGE GUIDANCE

Daily image verification is required before each fraction. Image verification can include 2-dimensional imaging with alignment to surgical clips, CBCT with alignment to cavity and breast contour, and 3-dimensional surface imaging with alignment to breast contour. Without daily CBCT, we recommend use of a larger PTV expansion. Each facility will have its preferred technique based on availability and applicability. Because of widespread availability in today’s era, we would recommend daily CBCT for a center implementing PBI.

CONCLUSION

Five fraction external beam PBI is a highly effective treatment with limited toxicity and is appropriate for a large proportion of patients with early stage breast cancer following breast conserving surgery. Treatment can be easily administered in 5 to 10 days by facilities worldwide with standard linear accelerators. Standard IMRT planning techniques result in homogenous treatment plans with very low dose to normal tissue, limiting acute and late toxicities.

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