A meta-analysis of the efficacy and safety of accelerated partial breast irradiation versus whole-breast irradiation for early-stage breast cancer

Breast cancer was the most frequently diagnosed cancer and the most frequent cause of death from cancer in women [1]. Breast-conserving surgery combined with whole-breast irradiation (WBI) has been the gold standard therapy for patients with early-stage breast cancer, which can yield cancer outcomes comparable to mastectomy [2, 3]. WBI is usually delivered once per day over several consecutive weeks, making access to effective radiotherapy problematic for women with some socioeconomic barriers [4‐6]. As most patients with early-stage breast cancer are cured of their disease, long-term toxicities become more and more critical [2].

Recurrence patterns after breast-conservation surgery suggest that most local recurrences occur predominantly at or near the breast tissue adjacent to the post-excision lumpectomy cavity [7, 8]. Accelerated partial breast irradiation (APBI) only irradiates the tumor bed in one week or less, which is a very favorable treatment that can reduce the burden of care and make it more likely to be accepted by patients [9]. Moreover, due to the smaller irradiation range of APBI, it is expected to reduce toxicity and improve cosmetic effect and quality of life compared with whole-breast irradiation [10].

APBI technology was introduced into clinical practice in the 1990s [11, 12], several different techniques have been developed, including intraoperative irradiation (IORT) with electrons or photons, multicatheter or single brachytherapy, and external beam radiotherapy using intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3DCRT). Current treatment guidelines [13, 14] and previous meta-analysis of randomized trials [15, 16] regarding APBI mainly address brachytherapy and IORT, these techniques are resource-intensive and invasive, requiring specialized radiotherapy delivery systems and surgical procedures. However, external beam radiotherapy such as 3DCRT and IMRT are noninvasive and only need the widely used CT planning system and linear accelerator. Recently, a large randomized phase 3 trial main using 3DCRT [17] and another [18] using 3DCRT or IMRT in the APBI arm have been officially published, but their results are still controversial. APBI is only applicable to highly selected breast cancer with low-risk factors and has not been widely used in clinical practice.

Here, we performed a systematic review and meta-analysis of all those published randomized studies adopting the APBI for early-stage breast cancer with the primary aims being LR (local recurrence), NR (regional recurrence), safety, cosmetic efficacy, and long-term survival outcome compared with WBI.

After screening 692 records, a total of 38 studies were considered to meet the criteria for inclusion in the systematic review potentially. Ultimately, 14 publications reporting on outcomes from 10 studies were included in the analysis. The GEC-ESTRO study reported on efficacy [19], early toxicity and patient compliance [20], late side-effects and cosmetic results [21], and quality-of-life results in different publications [22]. Studies were published in 2013–2020, 15,500 patients with early-stage breast cancer, including 7758 in the APBI group and 7742 in the WBI group. The flowchart of the literature search and selection process is shown in Fig. 1, while the characteristics of the eligible studies and main outcomes are summarized in Tables 1 and 2.

Adjuvant whole-breast irradiation after breast-conserving surgery can significantly reduce the risk of local and regional recurrences and has shown a positive influence on overall survival especially for patients with an intermediate to high absolute risk for local recurrences compared to lumpectomy alone, which has become the standard treatment for early-stage breast cancer [3, 34, 35]. Although adjuvant radiotherapy after breast-conserving surgery is crucial, many studies have shown that local recurrences frequently occur near the primary tumor location. Consequently, it is considered that radiotherapy’s main benefits arise from irradiating partial breast around the surgical cavity [7, 36, 37].

Accelerated partial breast irradiation is performed by aiming radiation delivery to the surgical cavity and its surrounding 1–2 cm breast tissue, which is considered to be the tissue with the highest risk of tumor cell residue after breast-conserving surgery [17, 18]. There are numerous techniques for APBI, including external beam-based APBI; IORT with either gamma-rays, photons or electrons; brachytherapy (interstitial or intracavitary) [38]. Commonly fractionation schemes include 38 Gy in 10 fractions with external beam-based APBI, 20–21 Gy in one fraction with IORT, or 34 Gy in 10 fractions for brachytherapy [38‐40]. Because the irradiation range is narrowed and the α/β ratio of breast cancer cells is lower than that of other tumors [41], accelerated large-division irradiation does not significantly increase acute or late radiotherapy responses. At the same time, APBI shortens the total treatment time, saves medical resources, and reducing patients' treatment costs and waiting time, which is of great economic significance [9, 42].

Although APBI has many advantages, there is still no unified standard for its techniques, indications, and fractionation schemes. At present, several societies have published guidelines to define whether patients can perform APBI: those of ASTRO (American Society for Radiation Oncology), GECESTRO (European Society for Radiotherapy and Oncology), and ABS (American Brachytherapy Society)[13, 43, 44]. In addition to consistent standards regarding age ≥ 50 years, negative node status, and absence of lymphovascular space invasion. There is no general consensus on other criteria such as tumor size, molecular typing, lymph node invasion, and other characteristics [13, 43, 44]. Consequently, the current guidelines recommend that patients receiving APBI should be carefully selected according to their clinical characteristics.

We reviewed a previously published meta-analysis that included seven trials for a total of 7452 patients [16]. This meta-analysis includes a study published in 1993 on the use of single-electron beams for APBI irradiation [11]. We believe that the technical conditions of radiotherapy used at that time are significantly different from those used later, so we have only included the latest ten studies. This meta-analysis showed that there was a significant difference in the 5-year local recurrence rate between the two groups (HR = 4.5, 95% CI 1.78–11.61, P = 0.002). There was no significant difference in regional recurrence, systemic recurrence, overall survival, or mortality rates between the two groups. The two groups’ side effects and cosmetic effects were similar, but intraoperative radiotherapy seemed to have greater acute side effects [16].

A recent meta-analysis, the literature search that ended in January 2018, included a total of eleven publications reporting nine studies findings, but two of them were informal data from conference summaries [45]. Our study includes accurate data that have been officially published in both studies, as well as additional research on long-term follow-up survival data for intraoperative radiotherapy. This study used odds ratios (OR) in their meta-analysis of local recurrence, non-breast cancer mortality, overall survival, regional recurrence, contralateral breast cancer, disease-free survival rate, and toxicity. However, HR is the appropriate natural indicator of time-to-event data, and we believe that HR is more accurate than OR in survival analysis. Consequently, HR is extracted as much as possible in our study, and then meta-analysis is performed. Besides, this study performed a subgroup analysis according to radiotherapy techniques, such as EBRT (external beam radiation treatment), brachytherapy, IORT, and other techniques. The subgroup analysis may not be the most appropriate because of each subgroup, including only a small number of studies. However, we performed a subgroup analysis of local recurrence according to whether the patients received therapy with Radiotherapy Treatment Planning System (TPS). There were seven studies in the TPS group and three studies in the Not TPS group.

In this meta-analysis, we included ten studies that reported local recurrence and found significant differences in local recurrence rates (HR = 1.46; 95% CI 1.20–1.79, P = 0.0002; heterogeneity P = 0.14, I² = 33%). We also note that there is a slight heterogeneity between the included studies, which may be due to the choice of treatment techniques. A total of three studies used IORT, two of which used IOERT (Intraoperative Electron Radiation Therapy)[32], and the other used TARGIT (Targeted intra-operative radiotherapy)[23, 29]. Obviously, 3DCRT, IMRT or brachytherapy based on TPS system have an accurate definition of the target area or dose distribution, while IORT and TARGIT are not involved. Therefore, we performed a subgroup analysis according to whether the patients received therapy with Radiotherapy Treatment Planning System (TPS). The results showed that the studies of the subgroups were homogeneous (P > 0.1, I² = 0%). Compared with the total heterogeneity, the heterogeneity of the subgroups was significantly reduced after subgroup analysis, and there was a statistical difference between the subgroups (P = 0.002, I² = 90.0%), it is suggested that the main cause of heterogeneity could be the TPS technology. Subset analyses showed that without TPS, APBI could significantly increase LR rate (HR = 2.50, 95% CI 1.69–3.68, P < 0.00001; heterogeneity P = 0.42, I² = 0%). However, with TPS, there was no significant difference in LR between the APBI group and the WBI group (HR = 1.20, 95% CI 0.95–1.52, P = 0.13; heterogeneity P = 0.95, I² = 0%). Therefore, we made a assumption that although APBI showed significant disadvantages in local control (similar to the results of previous meta-analyses), the selection of appropriate radiotherapy techniques may eliminate this difference. Although, from the patient's perspective, perhaps the most convenient APBI technique is IORT, which requires only one irradiation during breast-conserving surgery. IORT can not only improve the treatment compliance of patients but also decrease the irradiation of healthy organs and reduce the cost of treatment. However, external beam-based APBI, such as 3DCRT, IMRT radiotherapy are widely available. Multiple randomized trials using this radiation technique have been published and achieved the desired results. Another TPS-based brachytherapy technique predominantly depends on the experience and skills of the treating physician and is only available inexperienced institutions. Consequently, perhaps external beam-based APBI is the most appropriate technology.

Because the endpoints and criteria of toxicity, cosmetic outcomes, and quality of life were not uniform, we only made a descriptive analysis of their results. Compared to WBI, APBI significantly reduced serious (≥ grade 2) early toxicities, especially regarding acute skin toxicity [18, 20, 28, 32, 33]. Although less acute toxicity was observed, the regimen used was associated with an increase in late normal-tissue toxicity and adverse cosmesis in the RAPID trial, which might be related to the twice per day treatment [18]. Two studies reported patients' quality-of-life results; APBI was not associated with worse quality of life than WBI [22, 27]. Overall, there was no significant difference in toxicity, cosmetic outcomes and quality of life between the two groups, the compliance and tolerance of the patients were well.

The main limitations of our meta-analysis are related to the included studies rather than the systematic review itself. Because there are significant differences in times and treatment methods for APBI and WBI, blinding of patients and/or outcome assessors was not possible. However, it should be considered that in this kind of intervention, masking is not possible. In addition, most studies do not have independent data analysts. We believe that the objective results are unlikely to be significantly influenced by the lack of investigator-blind and independent data analysts.

In conclusion, among patients who had received breast-conserving treatment for early-stage breast cancer, the rate of local recurrence was significantly higher for APBI than for WBI, but no differences in distant metastasis, breast cancer deaths, contralateral breast cancer, disease-free survival, and overall survival rates. Based on our preliminary investigation of radiotherapy techniques, we recommend that external beam-based APBI should be considered in the treatment choice for selected low-risk patients, that brachytherapy is only available in experienced institutions and intraoperative radiotherapy should be used with caution.