For patients who underwent breast-conserving surgery and received whole-breast radiotherapy, long-term results from large randomized trials confirmed equivalent efficacy and safety of HFRT and CFRT. However, for patients who underwent surgical mastectomy the scarcity of high-level evidence has resulted in only a few patients having received HFRT [13], and only one randomized study has compared HFRT and CFRT in breast cancer patients who underwent mastectomy [12]. Other evidence for the clinical application of postmastectomy HFRT schedule has until now only been available from case series, retrospective studies, or subgroup analyses from the START randomized trials. Thus, we performed this meta-analysis to determine the efficacy and safety of postmastectomy HFRT schedule on outcomes in women with breast cancer. This meta-analysis indicated that HFRT and CFRT were equally effective with respect to overall survival (OS), disease-free survival (DFS), locoregional recurrence (LRR), and distant metastasis (DM) after breast mastectomy.
In recent small retrospective cohort studies, HF PMRT was shown to be effective with acceptable toxicity [38,39,40,41]. In a recent phase 2 trial [42], 67 women with clinical stage II to IIIa breast cancer who received a HF PMRT regimen of 36.6 Gy over 11 fractions to the chest wall and the draining regional lymph nodes with a scar boost of 4 fractions of 3.33 Gy revealed that after a median follow-up of 32 months, patients with isolated ipsilateral chest wall tumor recurrences were 3.0%, the 3-year estimated overall survival was 92.0% (95% CI, 78.9~97.1), the 3-year estimated local recurrence-free survival was 89.2% (95% CI, 74.8~95.6), the 3-year estimated distant recurrence-free survival was 90.3% (95% CI, 79.7~95.6), and low toxicity was reported. In Lancet Oncology, 2019, Shu-Lian Wang [12] reports 5-year outcomes of a randomized, non-inferiority, open-label, phase 3 trial comparing postmastectomy HFRT (43.5 Gy over 15 fractions in 3 weeks) and CFRT (50 Gy over 25 fractions in 5 weeks) directed to the chest wall and the supraclavicular and level III axillary nodal region in 820 patients with locally advanced breast cancer (at least four positive axillary lymph nodes or T3–4 tumors). All patients underwent chemotherapy, 76.5% used hormonal therapy, and the primary endpoint was 5-year locoregional recurrence. After a median follow-up of 58.5 months, there were no significant differences in the 5-year cumulative incidence of locoregional relapse (8·3% [90% CI 5·8~10·7] VS 8·1% [5·4~10·6]), 5-year overall survival (84%[90% CI 80~88] VS 86% [82~89]) and 5-year disease-free survival (74% [95% CI 70~79] VS 70% [65~76]) between the HFRT and CFRT groups. Furthermore, there was no significant difference between the two groups in the incidence of acute or late toxicities, including symptomatic radiation pneumonitis, lymphedema, ischemic heart disease, late skin toxicity, lung fibrosis or shoulder dysfunction; however, fewer patients experienced grade 3 acute skin toxicity in the HFRT group than in the CFRT group (14 [3%] of 401 patients VS 32 [8%] of 409 patients, p < 0.0001). No brachial plexopathy or rib fractures were observed, and frequencies of lymphedema and shoulder dysfunction were also reassuringly low, at less than 1% of grade 2 toxicity for both events. These results suggest that the HF PMRT regimen is safe and effective for patients with high-risk breast cancer, with low toxicity and high local control rate [12].
For long-term survival of breast cancer patients, the late treatment toxicities are also important. The results of this study found that there were no differences in acute skin toxicity, acute lung toxicity, late skin toxicity, lymphedema, shoulder restriction, or late cardiac related toxicity between the two groups. And we also found that no grade 2/3/4 late lung toxicity patients were observed, and the incidence of grade 1 was very low in the included studies [12, 14, 15, 23, 28, 32, 35]. Further, the randomized trial result showed that late lung toxicity may be increased in patients after HFRT (P = 0.08), but it was not statistically significant, which is worthy of further follow-up and research. Many studies have shown that the incidence of grade 2–4 acute skin toxicity after HF PMRT is between 10 and 25% [12, 28, 38, 39, 42], and this meta-analysis showed that the incidence of grade 2–4 acute skin toxicity in 3456 patients across 23 trials was 17.3%, which in line with reported rates. Similar results were observed in the PMRT subgroup of the UK START study (12%, 513/4451), which compared to the CFRT group, there was no significant difference in lymphedema or moderate or marked breast/shoulder/arm symptoms, etc. in patients receiving HFRT [5, 6]. Another late toxicity that should be considered is cardiac-related toxicity in patients after HFRT. Previous studies have shown that the incidence of cardiovascular events in patients with breast cancer after radiotherapy is very low, and the use of HFRT was not observed to increase that risk compared to CFRT [43,44,45]. The 10-year follow-up results of the UK START studies revealed that fatal cardiac events in START A and START B were 1.3 and 0.5%, respectively, while the incidence of ischemic heart disease was low (0.7%), and there was no significant difference between these two groups [5]. The proportion of patients with the late cardiac related toxicity was higher (52.1%) in the Pinitpatcharalert [28] study that the meta-analysis indicated, with 3.0% (1/67) in the CFRT group and 3.0% (3/148) in the HFRT group reporting patient deaths from cardiovascular events. This proportion is higher than in previous studies, which may be due to the small number of patients included, but there was no statistically significant difference between these two groups. The meta-analysis in our study showed no significant differences in late cardiac-related toxicity between the two groups, consistent with the above findings, indicating that HFRT does not significantly increase the risk of cardiovascular related events in breast cancer patients.
A higher dose per treatment fraction might increase the risk of toxicities in the setting of regional nodal irradiation (RNI) [46], but hypofractionated RNI was not observed to increase toxicity in one randomized clinical trial [12]. Two recent studies reported that the efficacy and safety of hypofractionated RNI were acceptable [47, 48]. One was based on UK START trials, with 864/5861 patients who experienced adjuvant lymphatic radiotherapy (LNRT) (PMRT 202/864, 23.4%) assessed using the EORTC QLQ-BR23 scale, protocol-specific questions and by physicians [47]. The long-term results from START trials suggest that appropriately dosed hypofractionated LNRT is safe, according to patient and physician-assessed arm and shoulder symptoms, a conclusion consistent with the findings for > 2.0 Gy schedules delivered to the breast/chest wall [47]. Another retrospective study reviewed 257 patients with stage IIa to IIIc breast cancer receiving hypofractionated RNI, with 80.2% patients having PMRT, 99.6% undergoing chemotherapy, 81.3% having hormonal treatment, and 25.3% having anti-HER2 targeted therapy. The median follow-up time was 64 months (range, 11 to 88 months), and the 5-year OS, DFS, locoregional recurrence (LRR)-free survival, and distant metastasis (DM)-free survival was 86.6, 84.4, 93.9 and 83.1%, respectively. During study follow-up, no acute symptomatic pneumonitis, cardiac events, brachial plexopathy or rib fractures occurred, and the incidence of grade 2–4 lymphedema was 5.8% [48]. The above findings suggest that the HFRT schedule may be acceptable in breast cancer patients who require RNI. However, prospective trials are necessary to confirm these results.
Hypofractionated radiotherapy could help to contain the costs of cancer care by mitigating financial toxicity and can be performed in most radiotherapy centers, even at small-scale hospitals. Studies have reported that the cost of using hypofractionated whole breast irradiation (WBI) in the United States is 31.7% lower than that of conventional fractionated WBI [49], and one study in Asia also indicated that the total cost of treatment for hypofractionated WBI compared to conventional fractionated WBI was reduced by about one-third [50]. It should be noted that although hypofractionated PMRT is not the same as the target area irradiated by hypofractionated WBI, the treatment technique and radiotherapy fraction are similar, and it can still shorten the treatment cycle, reduce the time of patient trips to the hospital, and save medical resources, which is more cost-effective. This issue is even more important in low- and middle-income countries.
The inclusion and exclusion criteria of this study were strict, the literature search was comprehensive, and the results are highly credible, but the following limitations do exist: 1. Quality of the included studies was unequal, and the number of included studies was limited. There may be differences in the quality of surgery between studies, and the quality of surgery could not be evaluated. There are many methods for adjuvant treatment of breast cancer, and all adjuvant treatments could not be evaluated. 2. Included studies did not provide survival data for patients of different age, tumor stage, positive lymph node numbers, pathological type, estrogen/progesterone levels, and could not be further analyzed for their impact on efficacy. However, the clinical characteristics of the two groups of patients included in the study, including age, tumor stage, pathological type, estrogen and progesterone levels, HER2 status, postoperative chemotherapy, etc., were not significantly different, so the reliability of these results was still high. 3. Most of the current studies were retrospective (only one was an RCT), and the quality of research methods is unequal. There are differences in treatment methods, radiotherapy, loss of follow-up descriptions, etc. It is difficult to extract all treatment data and then evaluate them. 4. Some trials used outdated radiotherapy techniques, and the use of hypofractionation schedules is variable. 5. Limited follow-up times in these included trials, multi-center prospective clinical trials and long-term follow-up are still needed for verification.