1 INTRODUCTION

Breast cancer has overtaken other cancers as the most frequently diagnosed malignant disease, and is the leading cause of cancer mortality in women globally, with an estimated 2.3 million new cases per year [1]. Approximately 70%–80% of patients with early-stage nonmetastatic breast cancer can now be cured [2]. The cure rate has been increasing as a result of combined therapy, with radiotherapy playing a significant role. Postmastectomy radiotherapy (PMRT) is important for high-risk patients and has been confirmed to improve local tumor control and the survival rate [3]. Women who have undergone mastectomy, especially younger women, often require breast reconstruction (BR). The proportion of patients undergoing reconstruction after mastectomy in the US increased significantly from 26.94% to 43.30% between 2005 and 2014 (p < 0.01) [4]. Now that BR is being increasingly performed, radiation oncologists must deal with the difficulty of integrating PMRT with BR. Although PMRT may reduce the rate of local tumor recurrence, it may also increase the incidence of complications and prevent good aesthetic results from BR. Furthermore, although BR improves patient satisfaction, it also increases the complexity of PMRT and the irradiation dose to the surrounding normal tissues. There are still no standards regarding the optimal type of reconstruction for patients who require PMRT, the optimal timing of BR, or how to optimize radiotherapy techniques for patients undergoing BR. This review discusses and summarizes these issues in light of the latest literature.

2 SELECTION OF TYPE OF BR

Depending on the reconstruction material used, BR can be divided into autologous tissue (flap) reconstruction (ATR), implant reconstruction (IR), and reconstruction with a combination of two materials (e.g., latissimus dorsi muscle combined with an implant) [5]. ATR mainly uses a transverse rectus abdominus myocutaneous flap, latissimus dorsi flap, or other tissue flaps to reconstruct the breast, while IR mainly uses prostheses for reconstruction. There are several advantages and disadvantages to both ATR and IR. Although ATR typically requires only one procedure and creates a natural contour and soft texture, it is more invasive and difficult to perform and necessitates a longer recovery period. While IR is less complicated and leaves no scars in the donor area, it typically requires two or more operations and has risks, such as capsular contracture and implant rupture [5]. The overall condition of the breast, the patient's preferences, and the type of postoperative adjuvant therapy should be considered when selecting the type of BR.

The strength of evidence for most of the studies that have directly compared ATR with IR has been low to moderate. A 2011 meta-analysis that compared these two types of reconstructions found that the postoperative complication rate was lower with ATR than with IR when radiation was administered following mastectomy (odds ratio [OR] = 0.20, 95% confidence interval [CI]: 0.11–0.39) [6]. This finding is consistent with the results of the 2018 prospective multicenter Mastectomy Reconstruction Outcomes Consortium cohort study, which included 643 patients who underwent ATR and 1604 who underwent IR at any of 11 participating institutions [7]. In 622 patients who received radiotherapy, the 2-year complication rate was lower for ATR than for IR (OR = 0.47, 95% CI: 0.27–0.82, p = 0.007); furthermore, ATR had a lower reconstruction failure rate (1.0% vs. 18.7%) and a higher breast satisfaction score (63.5 vs. 47.7). Similarly, 2 years after surgery, radiation was associated with a 2.64-fold higher risk of complications in the IR group (95% CI: 1.77–3.94, p < 0.001) but with an equal risk in the ATR group (OR = 1.12, 95% CI 0.66–1.92, p = 0.67). A 2022 meta-analysis of 40 studies found clinically significant improvements in breast satisfaction and sexual well-being in patients who underwent ATR in comparison with those who underwent IR [8]. While patients who underwent ATR had a higher risk of venous thromboembolism, those who underwent IR had a higher risk of reconstruction failure and seroma at follow-up 1.5–4 years later.

Although all the abovementioned studies found that IR had higher reconstruction failure and complication rates than ATR when combined with PMRT, it is important to note that the strength of evidence in most of the studies was relatively low. In reality, IR is performed more frequently. According to a review of the US MarketScan database, the reconstruction rate increased from 46% to 63% between 1998 and 2007, with the increase being driven predominantly by the increase in IR [9]. In 2019, Hamann et al. [10] found that 84.6% of patients who underwent both PMRT and IR reported being willing to undergo the same reconstruction technique again. Furthermore, implant-based second-stage reconstruction may preserve the option of subsequent reconstruction, including ATR.

3 TIMING OF PMRT IN PATIENTS UNDERGOING BR

BR is classified as immediate, delayed, or delayed-immediate (Figure 1) depending on the timing of reconstruction [11]. In immediate BR, reconstruction is carried out simultaneously with total mastectomy in a single procedure under general anesthesia. The benefits of immediate BR include the potential to preserve critical anatomical elements, such as the breast skin and even the nipple and areola, lower surgery costs, and sparing patients the anguish of losing a breast. Delayed BR refers to BR that is performed a few months or years after a total mastectomy. Patients who have lost their breasts without immediate BR are more eager to undergo BR. If it is not clear whether radiotherapy is required during mastectomy, a tissue expander can be implanted first and then replaced with a permanent breast prosthesis or autologous tissue during BR according to the postoperative pathological results. This two-stage BR procedure is called delayed-immediate BR. More research is needed to clarify the optimal timing of PMRT in patients undergoing BR.

4 DEVELOPMENT OF RADIOTHERAPY TECHNIQUES FOR BR

From the radiation oncologist's perspective, the goal of a PMRT plan is to achieve optimal coverage of the target volume while minimizing the irradiation dose to normal tissues. Previous studies have shown significant reductions in chest wall coverage, internal mammary node (IMN) coverage, and avoidance of the heart and lung in patients who undergo immediate BR and PMRT in comparison with patients who undergo PMRT without immediate BR, especially in those with left-sided lesions [39, 40]. However, more recent studies have reached different conclusions. In 2013, Chung et al. [41] found that it was feasible to deliver an adequate dose to the reconstructed breast using standard field arrangements regardless of the laterality of the treatment plan or the type of reconstruction but mentioned that irradiation of the IMN may increase the dose to the heart. In 2012, Ohri et al. [42] analyzed the impact of BR on radiotherapy plans from the perspective of the dose-volume histogram. They found that the treatment technique, not BR, was the major determinant of the target coverage and the dose to normal tissues. However, irradiation of the IMN significantly increased doses to the heart and lungs (all p < 0.05). Irradiation of the IMN is clearly a key factor in determining whether PMRT can achieve the best curative effect. Fortunately, other studies have demonstrated that BR does not affect the quality of PMRT plans even with IMN irradiation. A retrospective study by Ben-David et al. [43] evaluated the quality of radiotherapy plans in 29 patients who underwent immediate BR with implants. Two separate radiotherapy plans were designed for each patient based on the inclusion or exclusion of IMN. Comparing the two plans, they found that good coverage of the reconstructed breast (both ≥96.9%) was achieved with or without the inclusion of IMN, while heart and lung doses were low (the mean dose to the heart was <1.56 Gy and the mean total volume of lung receiving a dose of ≥20 Gy [V20] fluctuated between 13.8% and 19.47%). In 41 patients who underwent immediate breast expander reconstruction and PMRT, Koutcher et al. [44] found that the mean lung V20 was 13% (range, 3–23), and the mean dose to the heart was 2.81 Gy (range, 0.53–9.60). Patients with left-sided lesions who underwent IMN irradiation had a mean lung V20 of 18% and a mean dose of 8.04 Gy to the heart. Although IMN irradiation increases the doses to the lungs and heart, the doses are within acceptable ranges.

As awareness of the risk factors for breast cancer has increased, so has the need for bilateral mastectomy and bilateral BR [45, 46]. This also raises the question for radiation oncologists of whether contralateral/bilateral BR makes it more difficult to administer radiation therapy. As early as 2014, Ho et al. [47] found that bilateral IR did not affect the quality of postoperative radiation plans. Their study included 197 patients who underwent radiation therapy and BR, 51% of whom underwent unilateral reconstruction and 49% underwent bilateral reconstruction. Chest wall coverage was good in up to 90% of patients in their entire cohort. Multivariate analysis found that the presence of contralateral implants did not result in higher irradiation doses to the heart or lungs (p = 0.54). However, it should be noted that 14% of patients who underwent bilateral reconstruction still received radiation with contralateral implants. Furthermore, Jagsi et al. [7] found that bilateral reconstruction was a risk factor for breast complications at 1 and 2 years, postoperatively. These findings suggest that we need to find ways to reduce irradiation to contralateral implants. There are few studies on this topic, and the current practice is to reduce irradiation to the contralateral implant or increase coverage of the IMN by moving the contralateral implant away from the treatment area or reducing the volume of the tissue expander [47-49].

PMRT has undergone a transition from two-dimensional conventional and three-dimensional conformal techniques to newer techniques, such as intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and proton radiation therapy [50, 51]. These three techniques have been shown to improve the quality of radiotherapy plans for patients undergoing BR [52, 53]. Compared with three-dimensional conformal radiation therapy, IMRT and VMAT can deliver different doses to different target areas of the chest wall and lymph nodes, which can improve the uniformity of dose distribution in the target area and avoid high doses to the heart and lungs [54, 55]. VMAT has been shown to significantly reduce doses to the lung, heart, and contralateral breast/implant in patients with left-sided breast cancer when combined with deep inspiration breath-hold [56, 57]. However, breast radiotherapy with IMRT or VMAT increases exposure to large low-dose areas (≤5 Gy) in the chest, which may increase the incidence of radiation-related secondary tumors [58]. Further studies are required to determine the long-term complications of IMRT and VMAT. Compared with photon therapy, proton therapy, as a result of its unique physical and biological properties, can significantly reduce the radiation dose to normal tissues around the tumor, such as the heart and lungs, without reducing the dose to the tumor. Lower radiation doses to the heart and lungs are associated with lower risks of late cardiac events and secondary primary tumors [59-62]. Furthermore, proton therapy can be used to reduce the dose to surrounding normal tissue and avoid poor clinical target coverage in patients with IMN irradiation or left-sided breast cancer [63-65].

Different radiation modalities, fractionations, and the use of a local boost or bolus may be crucial determinants of the ultimate cosmetic result in women undergoing BR. In patients undergoing mastectomy and BR, conventional fractionated radiation is typically administered at the recommended dose of 45.0–50.4 Gy in 25–28 fractions. Some studies have shown that hypofractionated radiotherapy after mastectomy is non-inferior to conventional fractionated radiotherapy, which has led to increased interest in hypofractionated radiotherapy in BR [66]. A retrospective study in South Korea published in 2022 compared the impact of hypofractionated radiotherapy (2.4–2.7 Gy/fraction) with that of conventional fractionated radiotherapy (1.8–2.0 Gy/fraction) in 396 patients undergoing BR [67]. The median follow-up duration was 35.3 months. The median dose to the whole breast or chest wall was 44.3 Gy (range, 40.5–48.6) for hypofractionated radiotherapy and 50.3 Gy (range, 50–66) for conventional radiotherapy. Hypofractionated radiotherapy appeared to be comparable with conventional fractionated radiotherapy in terms of the incidence of breast-related complications in patients who underwent any type of BR. However, prospective studies are needed to confirm this finding. Khan et al. [68] enrolled 67 patients in a prospective study, 61% of whom underwent BR. Patients received hypofractionated radiotherapy consisting of a total dose of 36.63 Gy in 11 fractions. Some patients received additional local boosts of 4 fractions of 3.33 Gy. The median follow-up duration was 32 months. No serious toxicity was found, and the incidence of reconstruction-related complications was 32%, which is consistent with the findings of previous studies [69, 70]. Two prospective, randomized, controlled Phase III clinical studies comparing hypofractionated radiotherapy (42.56 Gy in 16 fractions) and conventional fractionated radiotherapy in patients undergoing BR are currently under way (NCT03414970 and NCT03422003). In theory, it makes sense to deliver higher doses to areas with a higher risk of local recurrence, such as radiation using local boosts or boluses in high-risk areas, but there may be an increase in the incidence of reconstruction complications. Naoum et al. [71] retrospectively investigated the effect of a chest wall boost on the incidence of reconstruction complications and the rate of disease control in 746 patients who underwent PMRT and BR; 379 received a chest wall boost and 367 did not. They found that radiation with a chest wall boost was associated with an increased risk of IR failure. Furthermore, administration of chest wall boost radiotherapy did not improve the local tumor control rate, even in high-risk patients. These findings suggest that omitting a chest wall boost in patients undergoing PMRT may improve the cosmetic outcome of BR without compromising local tumor control. This finding is consistent with the result of a single-center retrospective study reported in 2018 American Society for Radiation Oncology. The study included 730 patients who underwent BR between 1997 and 2001, of whom 43.2% received PMRT with a chest wall boost and 56.7% received PMRT without a boost. The respective median follow-up durations were 62 months and 75 months. The investigators found that the absence of a chest wall boost did not reduce the local tumor control rate but improved the outcome of BR. In the presence of tissue expanders or flaps, there is still considerable disagreement among US radiation oncologists about whether to use a bolus [72]. In patients with skin involvement, a bolus is usually preferred for skin coverage [73]. There are fewer studies on whether a bolus affects BR. A recently reported small retrospective study that included 25 patients who underwent two-stage BR and received a bolus in PMRT found that adding a bolus significantly increased the reconstruction failure and infection rates in the first stage of BR [74]. Large randomized controlled studies are needed to clarify the effect of boluses on BR.

5 CONCLUSION

PMRT and BR have become important components of treatment in patients with high-risk breast cancer after mastectomy. Existing studies do not clarify the optimal type of BR or the optimal timing of PMRT. ATR appears to be more resistant to radiotherapy than IR, but IR preserves the option of choosing another type of reconstruction later. The longer the interval between PMRT and BR, whether autologous tissue-based or implant-based, the lower the incidence of reconstruction-related complications. More prospective studies are expected to provide more definitive answers in these areas. At present, the choice of BR type and the timing of PMRT should be carefully considered based on the patient's tumor status, physical condition, cosmetic requirements, quality of life, and other factors to minimize tumor recurrence and reconstruction complication rates and improve patient satisfaction.

AUTHOR CONTRIBUTIONS

Honghong Zhang: Writing—original draft (equal); writing—review & editing (equal). Dandan Song: Writing—original draft (equal); writing—review & editing (equal). Liangxi Xie: Conceptualization (supporting); writing—review & editing (equal). Ning Zhan: Writing—review & editing (supporting). Wenjia Xie: Conceptualization (equal); writing—review & editing (equal). Jianming Zhang: Conceptualization (equal); funding acquisition (lead); supervision (lead).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Not applicable.

INFORMED CONSENT

Not applicable.