Patients are increasingly turning their attention to treatment-related adverse reactions, convenience, cost, and cosmetic effects following the continuous improvement in the efficacy of BCS and radiotherapy. Some researchers have tried to reduce the number of radiotherapy sessions. Wang et al. [1] proposed a hypofractionated 3-week schedule of postmastectomy radiotherapy to reduce the time of postoperative radiotherapy. However, the 3-week EBRT is still limited by the large radiotherapy area, damage to peripheral organs, and poor cosmetic results. The proportion of premenopausal breast cancer cases among Asian patients is significantly higher than in European and American patients. Patients may refuse to undergo supplementary EBRT because of the long EBRT time, high cost, and poor cosmetic outcomes, especially in less developed countries with limited and imbalanced medical resources. The breasts of Asian women are smaller and denser and are thus more suitable for IORT because they are radiated more thoroughly during surgery.
Studies postulate that IORT is superior to EBRT regarding side and cosmetic effects [10]. The local relapse and survival rates of IORT are non-inferior to those of EBRT. TARGIT and ELIOT are the two main types of IORT. They use single-dose radiation to the tumor bed during operation with low-energy X-rays and electron beam, respectively.
TARGIT-A trial was the largest international, multicentered, large-cohort, randomized controlled study that enrolled 3451 patients with breast cancer across 11 countries. The 5-year risk of local recurrence was 3.3% for TARGIT-treated patients versus 1.3% for EBRT-treated patients. However, the latter had more high-grade toxic reactions. There were no significant differences in the overall mortality between the TARGIT group and the EBRT group (3.9% vs. 5.3%), with a median follow-up period of only 2.4 years [3]. IORT was only suitable for a specific low-risk population because of the limited follow-up time of the TARGIT-A trial. Vaidya et al.[11] completed the long-term follow-up of the TARGIT-A trial with a median follow-up time of 8.5 years, covering 2298 patients. After five years of complete follow-up, the local recurrence risk was 2.11% for TARGIT-IORT compared to 0.95% for the EBRT group. There were no significant differences in local recurrence-free survival, mastectomy-free survival, distant disease-free survival, overall survival, and breast cancer mortality [11]. In the TARGIT-R study, a large-cohort retrospective study in North America, ipsilateral breast tumor
recurrence (IBTR) was 6.6% for all the patients after five years. The difference between the prospective randomized controlled TARGIT-A and TARGIT-R trials provides the necessary data for the application of IORT in the "real world." It also outlines the necessity of the "real world" study of IORT.
In the ELIOT study, 1305 patients from 28 medical centers across nine countries were enrolled and received IORT using the Mobetron® system. The study had a median follow-up time of 5.8 years. The local recurrence rate (LRR) for the IORT and EBRT groups was 4.4% and 0.4%, respectively. Besides, there were no significant differences in the five-year survival rates between the two groups (96.8%, IORT group vs. 96.9%, EBRT group). However, the IORT group showed significantly fewer skin-related side effects (p = 0.0002) than the EBRT group. Nonetheless, the researchers stated that the LRR could decrease to 1.5% with more careful inclusion criteria based on ASTRO [9].
Vicini et al.[12] conducted a randomized, 3-phased study (NSABPB-39/RTOB0413) that compared EBRT with APBI in 4216 patients who underwent mastectomy for ductal carcinoma in situ or invasive breast cancer (pN0 or pN1 with no more than three lymph nodes involved). The primary endpoint was IBTR. At ten years, IBTR was 4.6% for APBI-treated patients and 3.9% for EBRT-treated patients.
However, there are only a few that incorporate Asian populations, particularly Chinese populations. As such, studies including both Asian Chinese and other Asian populations are needed. Wang et al.[13] conducted a multicentered, randomized controlled trial to compare the hypo-fractionated radiotherapy (HFRT) with conventional EBRT after breast-conserving surgery amongst the Asian population with 734 patients from 4 Chinese institutions. The study had a median follow-up time of 73.5 months. The 5-year cumulative incidence of LR was 1.2% for HFRT versus 2.0% for EBRT. In the same line, the 5-year DFS and OS were 93.0% and 97.5% for HFRT, compared with 94.1% and 98.0% for EBRT, respectively.
The recommended criteria by the American Society of Therapeutic Radiation Oncology (ASTRO) [14], European Society of Therapeutic Radiation Oncology (ESTRO) [15], American Brachytherapy Society (ABS) [16], and American Society of Breast Surgeons (ASBrS) have been previously compared [15]. There is no generally accepted guideline for the treatment of the IORT of breast cancer patients. Different countries and organizations have various recommendations for IORT. Herein, low-risk patients with breast cancer were selected for IORT based on recommendations from the combination of the ASTRO consensus statement and TARGIT and ELIOT trials. Table 7 compares the three suitability criteria. Herein, we choose patients aged 40 years or older with unifocal tumor maximum diameter < 3 cm because Asian women have a higher incidence of premenopausal breast cancer. There was no metastasis in the sentinel lymph node biopsy. However, patients whose postoperative pathological examination revealed more than three axillary lymph node metastases were eliminated.
Previously, IORT has been found to be safe and feasible amongst the Chinese Han population, with a median follow-up of 51.8 months [17]. Herein, 451 patients were enrolled from 4 hospitals in China. The longest follow-up time was 11.9 years. It is the largest multicenter IORT study in China with the longest follow-up time. There are many previous EBRT trials with numerous patients and long follow-up time because it has been the standard treatment after BCS. Cognizant of this, we choose some of the earlier trials for comparison purposes. Herein, the IBTR was 1.5%, LRR was 2.8%, and the OS was 99.1%. These findings were comparable with those of EBRT clinical trials. These findings confirmed that the efficacy of TARGIT and ELIOT is non-inferior to that of EBRT. There were no significant differences in overall survival after TARGIT-IORT and ELIOT-IORT (Fig. 1). However, there are fewer skin adverse effects after IORT than EBRT [8, 9]. In this study, 27.7% of the patients showed mild skin pigmentation and fibrosis, but few severe fibrosis. Another 4.6% of patients had pulmonary fibrosis but no severe radiation-related toxicity. Good to excellent cosmetic outcomes were 63.0% of patients in the first three months after surgery, 83.7% at 1-year post-surgery, and 82.8% at 5-year post-surgery. These findings were comparable with those of the previous IORT studies.
Notably, this study compared the pre-excision IORT and post-excision IORT. In 301 hospital, ELIOT was delivered before lumpectomy. Pre-excisional IORT delivery to the entire tumor reduces TARGIT coverage problems and localization and improves the radiation dose distribution. The cosmesis, toxicity results, and local control have previously been reported [18, 19]. The University of North Carolina is the first registered center to deliver ELIOT to the tumor before surgical excision. However, the 53 patients who received IOERT alone showed 3-year, 5-year, and 6-year local recurrence rates of 8%, 13%, and 15%, respectively [18]. The study attributed the high local recurrence rates to under-estimating intraoperative tumor margins because of delivering ELIOT before excision and at a lower prescription dose. Herein, we compared the outcomes of pre-excision IORT and post-excision IORT. There were no significant differences in local recurrence, metastases, and cancer-related death rates. Based on previous studies, pre-excision IORT is associated with high local recurrence. As such, continued enrollment of patients in well-designed clinical studies is suggested.
Notably, we compared the survival results if patients in this study were selected based on the ASTRO criterion. In the ASTRO criterion, IORT should be delivered to patients belonging to the "Suitability" category of APBI. The "Suitability" category of patients is comprised of patients who are 50 years or older. The patients should have a tumor in the Tis or T1 stage. DCIS could be included when the size ≤ 2.5 cm and resected with margins negative at ≥ 3 m. In the ELIOT study, patients with invasive cancer fitting the "suitability" criteria had a low rate of LRR at approximately 1.5%, pointing out the importance of patient selection. Herein, the 208 patients who met the criteria of "suitability" had an LRR of 2.4%, OS rate of 99.5%, and DFS rate of 98.1%. However, there were no significant differences in LRR, DFS, and OS between patients aged 40 and 50 years older (p༞0.1). Cognizant of this, we concluded that the age range suitable for IORT should be extended to 40 years and older in Asian women, especially Chinese women. As such, many patients can benefit from this affordable treatment even in less developed countries with limited medical resources.
Considering the social and economic benefits, IORT is more economical and environmentally friendly than EBRT. Coombs et al.[20] assessed the environmental and social benefits of IORT with patients in the TARGIT-A trial. Introducing TARGIT helped patients in the UK to significantly save time, cost, and fuel and reduce CO2 emissions. Vaidya et al.[21] also reported that TARGIT-IORT gained 0.18 incremental quality-adjusted life-years (QALY) compared to EBRT, thus affirming the TARGIT-IORT is a dominant approach over EBRT.
Nevertheless, this study was limited by several factors. Differences in devices and follow-up time in the four hospitals limited the comparisons. However, a series of factors contribute to our study's validity, including potentially more uniform disease diagnosis, a higher degree of control in treatment implementation, and precise quality assurance, data collection, and follow-up. This limitation was addressed using the same criteria for the patients' follow-ups regardless of the hospital the surgery was done. Second, since the first IORT was used in 2008, some patients were lost in this process. And the criteria of "low-risk" patients have been extended since then.
Notably, this study was not randomized but rather a "real-world" retrospective study reporting outcomes of Chinese patients treated with IORT in China's routine clinical practice. As such, it provides a theoretical basis for future prospective studies.