The Role of Radiotherapy Fractionation And Volume In Patients With Early Breast Cancer After Conserving Surgery: A Systematic Review And Network Meta-Analysis

Background (cid:0) Hypofractionated whole breast irradiation (HF-WBI) can achieve the same treatment effect as conventional fractionated whole breast irradiation (CF-WBI) within limits , without increasing adverse reactions. Because of its characteristics of reducing the number of radiation therapy (RT) during the COVID-19 Pandemic, it is recommended as the rst choice of treatment for patients with early breast cancer after breast conserving surgery. However, the choice of RT is still under exploration. Here, we conducted a network meta-analysis to evaluate the problem comprehensively using data from new randomized trials. Methods: We analyzed data from eligible studies for published events for ipsilateral breast tumor recurrence (IBTR), distant metastasis, total deaths, and non-breast cancer-related deaths. Statistical analysis was performed using a xed-effects or random-effects model in cases of low and high heterogeneity, respectively. Network meta-analysis was conducted using a node-splitting model for two-category data among three RTs based on a Bayesian approach. Results: 16 studies with 23,418 patients were included. For IBTR, pairwise comparison showed that CF-WBI was signicantly better than PBI, and HF-WBI was similar to CF-WBI. HF-WBI was superior to PBI, but the difference was not signicant. However, indirect comparison of three RTs by network meta-analysis showed that HF-WBI was signicantly better than PBI (OR=0.67, CI95%: 0.46–0.95). Paired and network meta-analyses found no signicant differences in other endpoints among three radiotherapies. Conclusion: This meta-analysis demonstrated PBI was associated with increased IBTR compared with HF-WBI or CF-WBI in early-stage breast cancer patients. tumor recurrences (IBTR), distant metastases, total deaths, and non-breast cancer-related deaths recorded at the endpoints in each included study. IBTR included tumor-bed relapse and new tumors in the ipsilateral breast. metastasis of breast cancer was metastases at all sites outside the quadrant where the tumor was acute and late examined in systematic


Background
Changes in radiation therapy (RT) fractionation have long been studied in relation to various types of cancer, including breast cancer. The standard treatment for early breast cancer is breast-conserving surgery supplemented by whole-breast irradiation (WBI) and appropriate systemic therapy. However, a long course of conventional fractionated WBI (CF-WBI) for 5-6 weeks not only increases the economic burden on patients, but also affects the turnover of medical resources, thus limiting the popularity of breast-conserving surgery. Breast cancer tissue is as sensitive to fraction size as dose-limiting healthy tissues, so RT schedules can be greatly simpli ed by the delivery of fewer, larger fractions without compromising effectiveness or safety, and possibly improving both [1]. Moderate hypofractionated WBI (HF-WBI), de ned as a daily dose of 265-330 cGy, is delivered in 13-16 fractions [2]. Four large randomized controlled trials demonstrated that HF-WBI provided equivalent local control and overall survival to CF-WBI [1][2][3][4]. The American Society for Radiation Oncology (ASTRO) guidelines in 2018 therefore broadened the HF-WBI adaptive population, with no restrictions on age, stage, or chemotherapy. A scheme of 40.0-42.5 Gy/15-16 fractions was suggested [5]. National Comprehensive Cancer Network guidelines currently recommend that WBI should be given priority to HF-WBI scheme.
However, HF-WBI is only used in 34.5% of patients in the United States [6], and in as few as 12.1% of patients in China [7]. The slow adoption of HF-WBI in Asia and the United States may be related to physicians' concerns about the cosmetic side effects, especially when used in conjunction with tumor-bed boost and chemotherapy, or its use in patients with different breast sizes, or the absence of validation outside Canada and the United Kingdom [6]. Several randomized controlled trials are currently comparing the effects of HF-WBI and CF-WBI in terms of local tumor control, breast appearance (cosmesis), late toxicity, overall survival, and patient satisfaction [8][9][10][11][12][13].
On the other hand, analysis of local recurrence in patients treated for early breast cancer indicates that most recurrence occurs at the initial tumor location [14][15][16][17]. This suggests that irradiation of the tumor bed alone may be equally effective to WBI, with fewer side effects. Multiple randomized trials using different techniques have provided con icting results for tumor control, toxicity, and survival, mainly due to the heterogeneity of the trials and small sample sizes [18][19][20][21][22][23][24][25][26]. Based on these trials, ASTRO and the German Association of Radiology Oncology produced their accelerated PBI (APBI) criteria for patient selection and recommendations for irradiation methods [27,28]. Over recent decades, increasing attention has been paid to the dose-dependent effects of WBI on major coronary artery events [29,30] and secondary malignancies, including lung cancer [30]. PBI is presumed to reduce the occurrence of these late adverse events by reducing the radiation dose to the corresponding organs.
Several new trials have published results, while several large trials have updated longer follow-up results. The interventions to be compared are more than 2 (in this case, 3) and not all articles report all three single comparisons (PBI vs. CF-WBI, PBI vs. HF-WBI, and CF-WBI vs. HF-WBI), so network meta-analysis is done.
We conducted a comprehensive assessment of three RT modalities (PBI, HF-WBI, and CF-WBI) based on the results of recently published trials and update long-term follow-up trials data to evaluate and compare the effectiveness of PBI, HF-WBI, and HF-WBI.

Methods
This meta-analysis was carried out in accordance with the Cochrane Collaboration Handbook of Interventions Systematic Reviews [31] . The study followed the PRISMA reporting guidelines [32]. This review was prospectively registered in the PROSPERO database (Registration Number CRD42020219183).

Study inclusion/exclusion criteria
After the literature search, we included CF-WBI, HF-WBI, and PBI as the interventional postoperative RT arms in patients with early breast cancer. We pooled the results of different PBI techniques, such as external-beam radiation, intraoperative RT using electrons or photons, as well brachytherapy, including single-or multi-catheter-based approaches. The patients had to have undergone breast-conserving surgery and to have histologically con rmed primary breast cancer, either invasive or in situ breast cancer. The boost was assessed by the physicians in each study according to the risk of recurrence. Adjuvant systemic treatments were allowed. The included trials were published after 1 January 2000, to include comparable modern technologies. We excluded trials that compared different HF-WBI radiotherapy. The FAST [8] and FAST FORWARD [33] studies shortened 3-5 weeks of treatment to just 1 week, to explore the e cacy and safety of single-week ultra-hypofractionation. We included the FAST study but excluded the FAST FORWARD study in our analysis, because of the lack of a control arm. The TARGIT group recently updated the long-term results for the post-pathology or delayed-treatment subgroup, and we therefore split the trial into an original pre-pathology group and a delayed group, to allow the most appropriate estimation of the desired comparison 22,23 . The START study included two studies, Start A and Start B. Data for the longest follow-up period were published jointly in 2013. According to the authors' intention, we obtained data for the two studies from the joint paper 9 .

Data extraction
The data were extracted by two independent reviewers (Chen and Yang). A third reviewer resolved any disagreements (Chang). 16 studies with 23,418 patients were included. The outcome indicators in this study were the number of ipsilateral breast tumor recurrences (IBTR), distant metastases, total deaths, and nonbreast cancer-related deaths recorded at the endpoints in each included study. IBTR included tumor-bed relapse and new tumors in the ipsilateral breast.
Distant metastasis of breast cancer was de ned as metastases at all sites outside the quadrant where the tumor was located. Studies evaluating acute and late side effects and cosmetic effects used different evaluation criteria. It was therefore not possible to classify these indicators, which will be examined in another systematic review.

Risk of bias assessment
Two review authors (Chen and Yang) independently evaluated all relevant clinical studies for methodological quality. Each review author performed this assessment using the Cochrane Collaboration's Risk of Bias tool, which included quality of random allocation concealment, description of dropout and withdrawal, intention-to-treat analysis, and blinding procedures for treatment and outcome assessments [34]. A third reviewer resolved any disagreements by discussion (Chang).

Statistical analysis
Statistical analysis was performed using the GeMTC package in R (version 4.0.2). A node-splitting model [35] for two-category data among all three intervention arms based on a Bayesian approach was established. Odds ratios (OR) with 95% con dence intervals (CI) were calculated to determine the favored arm. Network consistency was analyzed by calculating the ratio of direct and indirect treatment effects within each comparison, with 95% CIs. If the 95% CI was >1.00 or < 1.00, the difference was considered signi cant (p<0.05). I 2 was used to assess the risk of bias in each model. I 2 < 50% means that there is a low risk of bias in the model.

Study characteristics
The owchart with the process of the studies selection is detailed as shown in Figure 1. 16 studies retrieved ful lled the inclusion criteria for this review (Table   1). A total of 23,418 patients were included, most of them with node negative, hormone receptor positive, tumor stage T1-T2 and N0 low-risk breast cancer patients. The intention-to-treat principle was respected for all analyses. Hypofractionated doses ranged from 2.7 to 6.0 Gy and total doses from 28.5 to 43.5 Gy. Tumor bed boosting and regional lymph node irradiation were not permitted in some trials, and mandated in others. Except for the natural defect blinding, all studies were considered as high quality and low risk of bias. Although there were some differences in patient selection criteria, adjuvant therapy regimens and the RT technique included in the trial, local control rates were similar in the CF-WBI group, suggesting that it may be a way to control differences in selection [1,[8][9][10][11][12][13][18][19][20][21]36].

Distant metastasis
Thirteen studies reported distant metastasis, including ve studies for HF-WBI vs CF-WBI, six studies for PBI vs CF-WBI, and two studies for HF-WBI vs PBI. The network meta-analysis ( Figure 3)

Total deaths
Thirteen studies reported total deaths, including ve studies for HF-WBI vs CF-WBI, six studies for PBI vs CF-WBI, and two studies for HF-WBI vs PBI. Figure 4 shows the network meta-analysis of total deaths among three RTs, which was not statistically different between each other. There were no detectable heterogeneity between the trials (I 2 = 0).

Non-breast cancer deaths
Eleven studies reported non-breast cancer-related deaths, including four studies for HF-WBI vs CF-WBI, six studies for PBI vs CF-WBI, and one study for HF-WBI vs PBI. Figure 5 shows the network meta-analysis of non-breast cancer deaths among three RTs, which was not statistically different between each other.
There were no detectable heterogeneity between the trials (I 2 < 50%).

Conclusions
In summary, this meta-analysis demonstrated PBI was associated with increased IBTR compared with HF-WBI or CF-WBI in early-stage breast cancer patients, and further research is still needed to compare the adverse effects and cosmesis of three distinct RT approach. There were no statistically difference among the RTs in terms of distant metastases, total deaths, and non-breast cancer mortality. Acknowledgments: Xian Chen, Tong-Xin Yang and Yao-Xiong Xia contributed equally to this work.
Con icts of Interest: The authors declare no con ict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Ethics approval and consent to participate Not applicable Consent for publication Not applicable  Comparison of IBTR by forest plots with odds ratios using conventional pair-wise meta-analysis and network meta-analysis, and network meta-ranking. Circle and quadrats represent individual trials and pooled effect sizes with corresponding 95% con dence intervals. Figure 3