External Beam Partial Breast Irradiation Versus Whole Breast Irradiation for in Early Breast Cancer (cid:0) A Systematic Review and Meta-Analysis

Purpose Postoperative radiotherapy can reduce the recurrence of breast cancer. Postoperative radiotherapy is divided into whole breast irradiation (WBI) and partial breast irradiation (PBI) for early breast cancers. Due to the characters of saving time, money, and easy to deliver, external beams PBI (EB PBI) is brought into focus. However, the researches on outcomes, safety, and ecacy between EB PBI and WBI are still insucient. We concluded a meta-analysis for LRR, regional node recurrence, contralateral breast cancer, distant recurrence, mortality, less acute skin toxicity ( (cid:0) 1 grade), late skin toxicity and the cosmetic score of external beam partial breast irradiation (EB PBI) and whole breast irradiation(WBI) to develop a radiotherapy plan for early low recurrence risk breast cancer patients. Method We Study eligibility criteria are as vs All to process. distant recurrence(RR = 1.00; 95% CI, 0.63 to 1.59; p = 1.00; I 2 = 0%), non-breast second cancer (RR = 1.03; 95% CI, 0.50 to 2.16; p = 0.93; I2 = 83%), mortality(RR = 0.96; 95% CI, 0.60 to 1.55; p = 0.88, I 2 = 54%). EB PBI had worse cosmetic score (RR = 1.56; 95% CI, 1.04 to 2.34; p = 0.003, I 2 = 84%), less acute skin toxicity ( (cid:0) 1 grade) (RR = 0.17; 95% CI, 0.07 to 0.42; p (cid:0) 0.0001, I 2 = 87%) and late skin toxicity(RR = 0.65; 95% CI, 0.48 to 0.88; p = 0.005; I 2 = 27%) than WBI.


Introduction
Breast cancer ranks second of the world in cancer incidence and mortality, with more than 2.08 million new cases and more than 630,000 deaths in 2018 1 . Irradiation can signi cantly reduce ipsilateral tumor recurrence and mortality of early breast cancer after breast-conserving surgery [2][3][4] . The delay of radiotherapy after breast-conserving surgery was associated with a signi cantly increased risk of local recurrence 5 . NCCN guideline-recommended radiotherapy after most of the early breast cancer patients after surgery, especially for breast-conserving surgery 6 . For early breast cancer patients with low recurrence risk, Partial breast irradiation (PBI) is another choice than traditional whole breast irradiation (WBI) [6][7][8] . The proposed of PBI were based on that the recurrence and metastasis sites after breastconserving surgery is usually located around the primary tumor. About 90% of recurrence was located in 1 cm from the primary tumor 7,9−12 . PBI just covers the primary tumor and its surrounding 2-3cm area. PBI can shorten the time of radio-chemotherapy, reduce the treatment cost, and easy to deliver for most radiotherapy centers 13 . The above advantages and fewer irradiation tissues also improved patients' compliance with postoperative radiotherapy, chemotherapy, and life quality 5,14 . Although PBI had lower mortality without breast cancer recurrence, However, PBI had higher local recurrence and bad cosmetology outcomes than WBI in previous studies 15,16 20 found PBI or accelerated partial breast irradiation (APBI) has worse cosmetic and some late effects, but it has less acute skin toxicity.
PBI can be divided into brachytherapy PBI (implantation, single-cavity, multi-cavity balloons or combined application), intraoperative PBI (IORT), External beam PBI (EB PBI). However, EB PBI has the advantages of non-invasive and easy to deliver in most radiation centers 21 . It also had the shortest time and economic costs for patients than WBRT-B, WBI, WBI-accelerated, WBRT intensity-modulated, (APBI)-IC, APBI-HDR interstitial 22 . EB PBI has a huge application prospect of early breast irradiation than brachytherapy PBI and IORT. Up to now, no systematic meta-analysis on outcomes e cacy and toxicity effects of EB PBI and WBI have been reported. Recently, the latest results of the RAPID were published 23 , we concluded a meta-analysis for EB PBI and WBI for radiotherapy of early low recurrence risk breast cancer patients.

Methods
This paper is reported in accordance with the preferred reporting items for systematic reviews and metaanalyses (PRISMA) statement and was registered at the International Prospective Register of Systematic Reviews (number:156882).
Two independent reviewers collected the data independently. Then they determined the data be included together. We tried to contact the authors to get not reported data. For papers that were updated or republished, the newest data was abstract. Cochrane's Review Manager 5.3 (RevMan) was used to assess statistical variance, risk ratios, heterogeneity and sensitivity. Homogeneity and sensitivity analysis were not described in detail because that the study we included was limited and small.
At last 4 papers were included (Fig. 1, Table 1), and all of them are RCTs. The outcomes were about the local regional rate (LRR), regional node recurrence, contralateral breast cancer, distant recurrence, and mortality. The results of the cosmetic score, acute skin toxicity ( 1 grade), and late skin toxicity also was included in our meta-analysis. P values of less than 0.05 were considered statistically signi cant.

Regional node recurrence
We de ned regional node recurrence as recurrences of the axilla, supra clavicular fossa, and internal mammary chain. Meta-analysis show there was no statistic difference between EB PBI and WBI groups Yasmin Korzets et al 16 fond that EB PBI may have the best control of local recurrence than brachytherapy PBI and IORT. EB PBI has similar local recurrence rate(LRR) with WBI. But they didn't include outcomes of RAPID 23 and didn't evaluate regional recurrence, cosmetic score, acute, and late skin toxicity. Our study is the systematic meta-analysis of EB PBI versus WBI. We found that EB PBI had no signi cant difference in LRR, regional node recurrence, contralateral breast cancer, distant recurrence and mortality compared with WBI. These conclusions were similar to Yasmin Korzets's 30 and Liu's 18 study. But we found that EB PBI tends to increase the risk of LRR, decrease the risk of regional node recurrence, contralateral breast cancer, distant recurrence, and mortality, although all of them had no statistical difference between EB PBI and WBI groups.
The selection of PBI patients was controversial. NCCN, GEC-ESTRO, and UK guidelines recommend the patients suitable for PBI were as follows ( Table 2). Different guidelines have different Selection criteria for low-risk early breast cancer patients. The patients that could deliver PBI were early breast stages with low recurrence risk. More studies were exploring the application and outcomes of PBI. NCCN guidelines recommend PBI was considered in patients as follows. (1) Older than 50 years old, T1, Negative margin ≥ 2 mm, no LVI, ER-positive, and BRCA negative. (2) Low/medium nuclear grading. The measured size of DCIS detected by screening is less than 2.5 cm and the margin of the negative cutting edge is more than or equal to 3 mm. GEC-ESTRO is similar to NCCN guidelines. In addition to the above inclusion criteria, UK consensus statements recommend that tumor size ≦ 3 cm and negative her-2 could also be considered for PBI. The inclusion criteria of PBI are still under discussion.    31 . Irradiation induced the ATM kinase activated and p38 mitogen-activated protein kinase (MAPK) through reactive oxygen species (ROS), H2AX, and other DNA repair protein repair DNA damage by NHEJ, HR. Then, activating transcription factor nuclear factor kappa-B activates pRb by p16INK4A ultimately induces durable cell-cycle arrest. Upregulation of in ammatory and brotic mediating, epigenetic changes, and disruption of normal oxygen metabolism will increase cytotoxicity reactive oxygen species (ROS) that occur within hours to years of exposure to ionizing radiation 32 . Apoptosis and senescence in cells trigger brosis through signaling pathways 33 . The key stages in the metastatic are the appearance of circulating tumor cells (CTCs) seeding and colonizing distant tissues and organs. EMT helps the tumor cells deform into a more metastasizing form. EMT is highly correlated with TGF-β 34 . TGF-β takes an important role in the process of preserving normal tissues, sensitizing tumor, pro-oxidant, and pro-brosis 32,33 .
EB PBI has less acute skin toxicity ( 1 grade), similar late skin toxicity, and worse cosmetic score than WBI which similar to Hickey BE 20 et al 's study. Breast induration or brosis, atrophy, appearance changed, edema, the color of skin, fatty necrosis might affect the cosmetic score of EB PBI. The 4 studies we included in our meta-analysis were EB APBI vs WBI/WBI-accelerated. The dose of fraction of APBI mostly higher than WBI/WBI-accelerated which might induce worse toxicity in breast tissue. Patients in EB APBI groups got less irradiation exposure to normal tissue lead to less acute skin toxicity ( 1 grade). A higher dose of fraction and less irradiation exposure tissue affected cosmetic score and late skin toxicity.
Livi L 25 et al's study was the source of heterogeneity for acute skin toxicity because it has a minimum proportion of patients with acute skin toxicity in the EB PBI group. Moreover, all 3 studies show EB PBI would cause less acute skin toxicity ( 1 grade) than WBI.
The position of tumor bed will atrophy after surgery [35][36][37] . The accuracy of tumor bed in EB PBI was not similar to branch therapy and IORT. Moreover, incomplete coverage of potential tumor targets and increased exposure to normal tissues in EB PBI also needs to solve. The recommended PBI exposure range is 1-3cm around the tumor bed 23 , it might incomplete coverage of potential target areas 38 . The different center has a different target area delineation standard. Different medical personnel had different delineation target area. But EB PBI has the largest irradiation range than beachy PBI and IORT which bring EB PBI better prognoses than PBI and IORT 23 . IMRT/VMRT can better t the tumors than other technologies, the way of delivering irradiation will affect the results. Most PBI studies were about beachy PBI and IORT. But EB PBI was More economical, noninvasive, beautiful, easy to popularize.
In fact, increased irradiation exposure can kill potential cancer cells, but increased exposure to normal tissues such as heart, lung, and contralateral breast not necessarily lead to better outcomes. For PBI, the accurate selection of the population, the expansion of irradiation exposure range, and the adjustment of exposure mode still need to be further explored. There needs more study on EB PBI to help more and more early breast patients bene t from PBI. Figure 1 Study selection scheme. Forest plots for outcomes. A: Local recurrence rates; B: Regional node recurrence; C: Contralateral breast cancer; D: Distant recurrence; E: Non-breast second cancer; F: Mortality; G: Cosmetic score; H: acute skin toxicity ( 1 grade); I: late skin toxicity.