Building radiation-resistant model in triple-negative breast cancer to screen radioresistance-related molecular markers.

BACKGROUND: To build the triple-negative breast cancer (TNBC) radiation resistance model in vitro and vivo, and screen the molecular markers that related to radiation resistance. METHODS: We used X-ray to irradiate MDA-MB-231 cells repeatedly to build radioresistant cell (231-RR), then select one gemcitabine-resistance of MDA-MB-231 cell (231-GEM). We screen differentially expressed genes of these cell lines. Then, we would select 2 genes of them associated with DNA damage repair or cell cycle, and build RNAi lentivirus vector to knock down related gene. We also used X-rays repeatedly exposure TNBC tumor xenograft to build tumor with radioresistance properties, and then verify previously screening differentially expressed genes using IHC. Finally, we used The Cancer Genome Atlas (TCGA) database to validate the relationships between radioresistance related genes and the prognosis of breast cancer. RESULTS: We got 161 up-regulated genes and 156 down-regulated genes from three cell lines. Cellular results show the 231-cell with knock-down CDKN1A or SOD2 gene, its radiation sensitivity was significantly enhanced. We successfully got the TNBC xenograft tumor with radioresistance properties. Immunohistochemical results show that the radioresistance of tumor tissue with higher p21 (CDKN1A encoding protein) and SOD2 expression (P<0.01). The prognosis of patients with low SOD2 expression is better than that of high expression, but have no statistical significance (P=0.119); patients with low CDKN1A expression is significantly better than high expression (P=0.000). Multivariate cox analysis manifest that CDKN1A gene expression level is an independent prognostic factor in breast cancer patient (P=0.008). CONCLUSIONS: Construction of radiation resistance cell and xenograft tumor with radio-resistant properties model for radiation biology research is feasible. High SOD2 and CDKN1A is associated with the poor prognosis in breast cancer patients. These two genes could be used as a predicted makers of breast cancer radiation sensitivity.

Highlights on molecular targets for radiosensitization of breast cancer cells: Current research status and prospects.

In the past, searching for effective radiotherapy sensitization molecular targets and improving the radiation sensitivity of malignant tumors was the hot topic for the oncologists, but with little achievements. We will summarize the research results about breast cancer irradiation sensitization molecular targets over the past two decades; we mainly focus on the following aspects: DNA damage repair and radiation sensitization, cell cycle regulation and radiation sensitization, cell autophagy regulation and radiation sensitization, and radiation sensitivity prediction and breast cancer radiotherapy scheme making. And based on this summary, we will put forward some of our viewpoints.

Effectiveness of liposome bupivacaine for postoperative pain control in total knee arthroplasty: A PRISMA-compliant meta-analysis of randomized controlled trials.

BACKGROUND: Adequate pain control after total knee arthroplasty (TKA) enables quicker recovery and reduces readmissions and treatment costs. The aim of this study was to determine the effect of liposomal bupivacaine (LB) for postoperative pain control in patients prepared for TKA. METHODS: We searched for the reports that evaluating the effect of liposomal bupivacaine for postoperative pain control in patients prepared for TKA between March 1983 and May 2017 in the electronic database Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, and Ovid. The main outcomes were visual analog scale (VAS) at 24, 48, and 72 hours. The secondary outcomes were total morphine consumption, the length of hospital stay, range of motion, and the occurrence of nausea. RESULTS: Seven randomized controlled trials (RCTs) enrolling 825 patients, with 413 in the LB group and 412 in the control group, were included in this meta-analysis. Our results suggested that administration LB was associated with a reduction of VAS by 4.22 points at 72 hours after TKA (WMD = -4.22, 95% CI -7.47, -0.97, P = .011) on a 100-point VAS. What's more, LB can decrease the occurrence of nausea when compared with traditional bupivacaine by 18.3% (risk ratio  = 0.70, 95% confidence interval 0.55, 0.89, P = .003). LB was associated with an increase of the range of motion than traditional bupivacaine (P < .05). There was no significant difference between the VAS at 24, 48 hours, total morphine consumption and the length of hospital stay. CONCLUSIONS: Administration with LB was associated with pain-relieving effects and reduces the morphine-related complications (nausea). Due the limited number of the included RCTs, large number and high quality RCTs are still need to identify the effects of LB for pain control after TKA.

Prognostic factors in breast phyllodes tumors: a nomogram based on a retrospective cohort study of 404 patients.

The aim of this study was to explore the independent prognostic factors related to postoperative recurrence-free survival (RFS) in patients with breast phyllodes tumors (PTBs). A retrospective analysis was conducted in Fudan University Shanghai Cancer Center. According to histological type, patients with benign PTBs were classified as a low-risk group, while borderline and malignant PTBs were classified as a high-risk group. The Cox regression model was adopted to identify factors affecting postoperative RFS in the two groups, and a nomogram was generated to predict recurrence-free survival at 1, 3, and 5 years. Among the 404 patients, 168 (41.6%) patients had benign PTB, 184 (45.5%) had borderline PTB, and 52 (12.9%) had malignant PTB. Fifty-five patients experienced postoperative local recurrence, including six benign cases, 26 borderline cases, and 22 malignant cases; the three histological types of PTB had local recurrence rates of 3.6%, 14.1%, and 42.3%, respectively. Stromal cell atypia was an independent prognostic factor for RFS in the low-risk group, while the surgical approach and tumor border were independent prognostic factors for RFS in the high-risk group, and patients receiving simple excision with an infiltrative tumor border had a higher recurrence rate. A nomogram developed based on clinicopathologic features and surgical approaches could predict recurrence-free survival at 1, 3, and 5 years. For high-risk patients, this predictive nomogram based on tumor border, tumor residue, mitotic activity, degree of stromal cell hyperplasia, and atypia can be applied for patient counseling and clinical management. The efficacy of adjuvant radiotherapy remains uncertain.

The Chk1 inhibitor MK-8776 increases the radiosensitivity of human triple-negative breast cancer by inhibiting autophagy.

MK-8776 is a recently described inhibitor that is highly selective for checkpoint kinase 1 (Chk1), which can weaken the DNA repair capacity in cancer cells to achieve chemo-sensitization. A number of studies show that MK-8776 enhances the cytotoxicity of hydroxyurea and gemcitabine without increasing normal tissue toxicities. Thus far, there is no evidence that MK-8776 can be used as a radiotherapy sensitization agent. In this study, we investigated the effects of MK-8776 on the radiosensitivity of 3 human triple-negative breast cancer (TNBC) cell lines MDA-MB-231, BT-549 and CAL-51. MK-8776 dose-dependently inhibited the proliferation of MDA-MB-231, BT-549 and CAL-51 cells with IC50 values of 9.4, 17.6 and 2.1 µmol/L, respectively. Compared with irradiation-alone treatment, pretreatment with a low dose of MK-8776 (100-400 nmol/L) significantly increased irradiation-induced γH2A.X foci in the 3 TNBC cell lines, suggesting enhanced DNA damage by MK-8776, inhibited the cell proliferation and increased the radiosensitivity of the 3 TNBC cell lines. Similar results were obtained in MDA-MB-231 xenograft tumors in nude mice that received MK-8776 (15 or 40 mg/kg, ip) 26 d after irradiation. To explore the mechanisms underlying the radio-sensitization by MK-8776, we used TEM and found that irradiation significantly increased the numbers of autophagosomes in the 3 TNBC cell lines. Moreover, irradiation markedly elevated the levels of Atg5, and promoted the transformation of LC3-I to LC3-II in the cells. Pretreatment with the low dose of MK-8776 suppressed these effects. The above results suggest that MK-8776 increases human TNBC radiosensitivity by inhibiting irradiation-induced autophagy and that MK-8776 may be a potential agent in the radiosensitization of human TNBC.

Trastuzumab improves locoregional control in HER2-positive breast cancer patients following adjuvant radiotherapy.

The benefit of adjuvant trastuzumab in disease-free and overall survival for human epidermal receptor 2-positive (HER2+) breast cancer patients is well established. However, the effect of trastuzumab on locoregional control remains unclear, particularly in patients treated with adjuvant radiotherapy (RT). In this study, we investigated the locoregional benefit of trastuzumab in patients with HER2+ breast cancer after adjuvant RT.Using a single institutional database, we identified 278 patients with stage II/III invasive HER2+ breast tumors receiving adjuvant RT between January 2008 and July 2011. We compared the locoregional outcomes of 134 patients who received trastuzumab to 144 patients without trastuzumab within the same period. Clinical and biological factors that might impact on the locoregional benefit of trastuzumab were also assessed.At the median follow-up of 45 months, trastuzumab significantly lowered the risk of locoregional recurrence (LRR) with a 3-year LRR rate of 2.4% versus 7.5% for the cohort with and without trastuzumab (P = 0.019). Trastuzumab was associated with a more significant locoregional benefit in the hormone receptor-positive (HR+)/HER2+ subgroup, with a 3-year LRR of 0% versus 6.7% in the cohort with and without trastuzumab (P = 0.027). For HR-/HER2+ breast tumor patients, the 3-year LRR rate was still lower for the cohort with trastuzumab (4.7% vs 8.6%). However, statistical significance was not found (P = 0.179). Both univariate and multivariate analyses confirmed that trastuzumab treatment was the only significant predictive factor for LRR (hazard ratio, 4.05; 95% confidence interval, 1.07-15.35; P = 0.039).Adjuvant trastuzumab in addition to RT is associated with significant reduced LRR risk in HER2+ breast cancer.

The efficacy of postoperative radiotherapy in localized primary soft tissue sarcoma treated with conservative surgery.

BACKGROUND: To evaluate the efficacy of postoperative radiotherapy (RT) on local failure-free survival (LFFS), distant metastasis-free survival (DMFS) and overall survival (OS) in patients with localized primary soft tissue sarcoma (STS) and to identify prognostic factors. METHODS AND MATERIALS: Between January 2000 and July 2010, 220 consecutive patients with localized primary STS, who received conservative surgery with or without postoperative RT, were enrolled in the study. Survival curves were constructed by the Kaplan-Meier method and log-rank test was used to assess statistical significance. Multivariate analysis was applied to identify the prognostic factors. RESULTS: After a median follow-up of 68 months (range, 5-127 months), the 5-year LFFS, DMFS and OS were 70.0, 78.2 and 71.2 %, respectively. Tumor size, histological subtypes, margin status and postoperative RT were independent predictors for OS. Postoperative RT was associated with a significant reduced local recurrence risk versus surgery alone (hazard ratio [HR] = 0.408, 95 % confidence interval [CI] 0.235-0.707, P = 0.001), with 5-year LFFS of 81.1 and 63.6 %, respectively (log-rank, P = 0.004). The log-rank test showed that postoperative RT had a tendency of improving OS compared with surgery alone, with 5-year OS of 74.8 and 65.0 %, respectively (P = 0.089). Multivariate analysis demonstrated that postoperative RT significantly reduced mortality rate compared with surgery alone (HR = 0.512, 95 % CI 0.296-0.886, p = 0.017), especially in patients with liposarcoma (p = 0.034). CONCLUSION: Postoperative radiotherapy reduce both local recurrence and STS mortality in patients with localized primary STS. The efficacy of RT on survival warrants further prospective study.

Early Local Recurrence Presents Adverse Effect on Outcomes of Primary Breast Sarcoma: A Retrospective Study From Single Institute in China.

Primary breast sarcomas (PBSs) are spectrum heterogeneous sarcomas in breast and the optimal treatment for them is still under discussion. Our study was to investigate clinical characteristics and identify potential prognostic factors for this rare malignancy. The authors retrospectively reviewed 38 patients with PBSs between October 2000 and February 2014 in FuDan University Shanghai Cancer Center. Local control rate and overall survival (OS) were determined by Kaplan-Meier actuarial method. Univariate analysis and Cox proportional hazards model were applied to identify potential prognostic factors. With median follow-up of 40.19 months, 14 patients (14/38) were found with local recurrence. Extensive operation like mastectomy was not superior to local resection (P = 0.167). Three-year recurrence-free survival and OS rate were 61.9% and 89%, respectively. Larger tumor size and local recurrence were indicated as unfavorable prognostic factors in univariate analysis. Cox model identified narrow interval of recurrence free survival as an unfavorable factor (P = 0.048). Surgery remains crucial treatment for PBSs. Mastectomy, however, is not routinely necessary if clear margin could be achieved by local excision. Early recurrence indicates a poor OS.

Diagnostic performance of core needle biopsy in identifying breast phyllodes tumors.

BACKGROUND: A retrospective analysis of diagnoses was performed in patients with phyllodes tumors of the breast (PTB) who received preoperative core needle biopsy (CNB) and had breast surgery at Fudan University Shanghai Cancer Center from January 1, 2002 to April 1, 2013. The resulting data allowed us to compare the accordance between CNB and excision diagnoses of PTB patients and evaluate the accuracy of CNB in preoperative diagnosis. METHODS: Data from 128 patients with PTB who had undergone preoperative CNB and breast surgery were retrospectively analyzed. We reviewed the medical history, clinical follow-up data, and CNB diagnostic data. A diagnostic test was used to evaluate the sensitivity and specificity of CNB in diagnosing benign, borderline, and malignant phyllodes tumors. RESULTS: The accuracy of CNB for diagnosing PTB was 13.3% (17/128). Of the remaining patients, 98 (75.5% of the PTB patients) were diagnosed with fibroadenoma or fibroepithelial lesions. The sensitivity of CNB at diagnosing benign, borderline, and malignant phyllodes tumors were 4.9% (2/41), 4.2% (3/71), and 25.0% (4/16), respectively, whereas the corresponding specificity were 92.0%, 98.2%, and 100%, respectively. Some clinical features, such as large tumor size, rapid growth, or surgical history of fibroadenomas, were indicative of an increased possibility of PTB. CONCLUSIONS: CNB provides a pathological basis for the preoperative diagnosis of PTB, but it has a poor accuracy and offers limited guidance for surgical decisions. Considering CNB along with multiple histologic features may improve the ability to accurately diagnose PTB. An integrated assessment using CNBs in combination with clinical data and imaging features is suggested as a reliable strategy to assist PTB diagnosis.

Phyllodes tumors of the breast: diagnosis, treatment and prognostic factors related to recurrence.

Phyllodes tumors of the breast are rare tumor types that consist of 0.3-1.0% in all breast tumors. The naming and classification of breast phyllodes tumor have been debated for years. Based on the classification criteria modified by WHO in 2003, this review mainly introduced the clinicopathologic characteristics, pre-operational diagnosis and the treatment of breast phyllodes tumors, and also summarized the prognostic factors related to tumor recurrence.

Is internal mammary nodes irradiation as a part of breast cancer postoperative radiotherapy necessary?

Postoperative radiotherapy plays an important role in the multidisciplinary treatment of breast cancer. However, it remains a controversy whether it is necessary to carry out prophylactic internal mammary nodes irradiation (IMNI). This review will focus on this topic. In our opinion, the total risk of relapse should be considered during the decision-making on IMNI; in particular, IMNI is recommended for high-risk patients whose tumor is located at the central/medial area or in patients with positive axillary lymph nodes.

Early cardiac toxicity following adjuvant radiotherapy of left-sided breast cancer with or without concurrent trastuzumab.

PURPOSE: To evaluate the influence of concurrent trastuzumab on the cardiotoxicity in patients receiving left-sided adjuvant radiotherapy. MATERIALS AND METHODS: Medical records of stage I-III left-sided breast cancer patients, including 64 receiving concurrent trastuzumab with radiotherapy and 73 receiving radiotherapy alone were retrospectively reviewed. All of the patients had normal LVEF after adjuvant chemotherapy. Information of doses volume to cardiac structures was collected. Cardiac events were assessed according to CTC 2.0. RESULTS: Median follow-up of LVEF and clinical assessment of cardiac function from the initiation of radiotherapy was 6.7 months (range 3-60.9) and 26 months (range 6.4-60.9), respectively. Grade 1 LVEF dysfunction occurred in 5 (7.8%) and 3 (4.1%) patients of the concurrent-trastuzumab and radiotherapy alone cohort, respectively. Trastuzumab was the only significant factor influencing absolute LVEF decrease in univariate analysis. In multivariate analysis of concurrent-trastuzumab cohort, IMC radiotherapy and start trastuzumab during radiotherapy were independent risk factors. For concurrent cohort, mean heart dose, as well as D10-D30, D50-D55, V5-V20 of the heart and D30-D45, D65-D75, V6-V15 of the LV were significantly higher in patients developing LVEF dysfunction. CONCLUSIONS: Concurrent trastuzumab and left-sided radiotherapy is well tolerated in terms of cardiotoxicity in patients with normal baseline cardiac function after adjuvant chemotherapy. However, increases in mean dose and low-dose volume of cardiac structures are associated with a higher risk of acute LVEF dysfunction.

Management experiences of primary angiosarcoma of breast: a retrospective study from single institute in the People's Republic of China.

BACKGROUND: Primary angiosarcoma of breast (PAOB) is a rare and highly aggressive malignancy. There is no general agreement on optimal treatments or prognostic factors for this orphan disease. The objective of this study was to investigate the clinicopathologic features and management experiences of PAOB. METHODS: We performed a retrospective review of medical and pathologic records of 17 consecutive patients diagnosed with PAOB between January 2000 and February 2014 at FuDan University Shanghai Cancer Center. We evaluated the clinical characteristics, multimodality treatments, and associated clinical outcomes. RESULTS: A total of 16 patients were included in this retrospective study (median age at PAOB presentation 33.5 years, range: 19-56 years). Palpable tumor with or without breast skin ecchymosis presented as the most common initial symptom. All patients underwent surgery with curative intent. Median disease-free survival and overall survival (OS) were 9 months and 13.6 months, respectively. One-year and 3-year disease-free survival rates were 43.8% and 6.3%, with OS rates of 93.8% and 78.1%, respectively. High histologic grade indicated poorer OS by univariate analysis (P=0.01). However, neither adjuvant chemotherapy nor radiotherapy contributed to clinical outcomes in our series. CONCLUSION: PAOB is considered as an infrequent breast neoplasm with aggressive characteristics. Histologic grade and early metastasis (within 12 months after diagnosis) are associated with poor prognosis. Regardless of grade, additional benefit was not observed with adjuvant therapy.

Systematic review and meta-analysis comparing hypofractionated with conventional fraction radiotherapy in treatment of early breast cancer.

BACKGROUND: The purpose of this meta-analysis is to evaluate the efficacy and safety of altered radiation fraction size on outcomes for early breast cancer patients. METHODS: A search of MEDLINE, EMBASE, WEB OF SCIENCE, Cochrane Library and ClinicalTrials.gov was conducted. Quality of the randomized controlled trials (RCTs) or non-RCTs were evaluated according to Cochrane's risk of bias tool or Methodological Index for non-Randomized Studies (MINORS). Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated. Subgroup analysis was applied according to different fraction dose and sensitivity analysis was performed according to RCTs or non-RCTs. RESULTS: 23 studies were included in this systematic review. Meta-analysis demonstrated hypofractionation radiotherapy (HFRT) was associated with decreased grade 2/3 acute skin reactions compared with conventional fraction RT (CFRT), either 2.5-3.0 Gy per fraction or 5.0-6.5 Gy per fraction. HFRT with 2.5-3.0 Gy per fraction significantly decreased moderate/marked photographic changes in breast appearance compared with CFRT [RR = 0.80, 95% CI (0.70, 0.91), P = 0.001], while HFRT with more than 3.0 Gy per fraction significantly increased moderate/marked photographic changes [RR = 1.21, 95% CI (1.06, 1.38), P = 0.004]. In addition HFRT cost one-third lower than CFRT. Regarding to local regional recurrence, distant metastasis, overall survival, disease free survival, excellent/good cosmetic comes, symptomatic radiation pneumonitis, ischemic heart disease and symptomatic rib fracture, there was no significant difference between two arms. CONCLUSIONS: Based on available evidence, HFRT with 2.5-3.0 Gy per fraction should be the better choice for treatment of early breast cancer patients.

Dose coverage of axillary level I-III areas during whole breast irradiation with simplified intensity modulated radiation therapy in early stage breast cancer patients.

PURPOSE: This study was designed to evaluate the dose coverage of axillary areas during whole breast irradiation with simplified intensity modulated radiation therapy (s-IMRT) and field-in-field IMRT (for-IMRT) in early stage breast cancer patients. METHODS: Sixty-one consecutive patients with breast-conserving surgery and sentinel lymph node biopsy were collected. Two plans were created for each patient: the s-IMRT and for-IMRT plan. Dosimetric parameters of axillary areas were compared. RESULTS: The average of mean doses delivered to the axillary level I areas in s-IMRT and for-IMRT plan were 27.7Gy and 29.1Gy (p = 0.011), respectively. The average of V47.5Gy, V45Gy and V40Gy (percent volume receiving≥ 47.5Gy, 45Gy and 40Gy) of the axillary level I in s-IMRT plan was significantly lower than that in for-IMRT plan (p < 0.001). For for-IMRT plans, patients with upper tangential border to humeral head ≤2cm, breast separation >19.3cm and body width >31.9cm had significantly higher mean dose in axillary level I area (p = 0.002, 0.007, 0.001, respectively). CONCLUSION: Compared with for-IMRT plan, the s-IMRT plan delivered lower dose to axillary level I area. For centers using s-IMRT technique, caution should be exercised when selecting to omit axillary lymph node dissection for patients with breast conserving surgery and limited positive SLNs.

Diastolic Dysfunction Occurs Early in HER2-Positive Breast Cancer Patients Treated Concurrently With Radiation Therapy and Trastuzumab.

BACKGROUND: Left ventricular ejection fraction (LVEF) is used routinely to monitor cardiac dysfunction associated with breast cancer treatment. In this study the prevalence of early left ventricular diastolic dysfunction (LVDD) and its relationship to the dose-volume of the heart irradiated were evaluated in HER2-positive breast cancer patients undergoing concurrent trastuzumab and adjuvant radiotherapy (RT). MATERIALS AND METHODS: Data from 40 breast cancer patients treated with concurrent trastuzumab and left-sided adjuvant RT between September 2011 and October 2012 were collected prospectively. For comparison, 32 patients treated with concurrent trastuzumab and right-sided adjuvant RT and 71 patients treated with left-sided RT alone were collected retrospectively. Echocardiography was obtained before RT, immediately following RT, and 3 and 6 months after RT. Doses to the heart and left ventricle (LV) were quantified. RESULTS: Prior to RT with concurrent trastuzumab, 11 of 29 (left) and 8 of 25 (right) patients with normal baseline left ventricular diastolic function (LVDF) developed LVDD. In patients receiving left-sided RT alone, 12 of 61 patients with normal baseline LVDF developed LVDD. Dmean, D15-D40, D60-D70, and V3-V10 of the LV were significantly higher in patients who developed LVDD after concurrent trastuzumab and left-sided RT. In contrast, only two patients developed grade 1 LVEF decrease after both concurrent treatment and left-sided RT alone. CONCLUSION: Changes in LVDF compared with LVEF are more sensitive for early detection of cardiotoxicity. The dose-volume of the heart contributes significantly to the risk of LVDD in patients with left-sided breast cancer treated concurrently with trastuzumab. IMPLICATIONS FOR PRACTICE: Abnormalities in diastolic function are more sensitive than changes in the left ventricular ejection fraction for detecting acute cardiotoxicity and are related to the dose-volume of the heart irradiated in patients with left-sided breast cancer receiving radiotherapy concurrently with trastuzumab. This result highlights the importance of decreasing the dose-volume of heart irradiated as a protective strategy in the treatment setting of concurrent trastuzumab and radiotherapy. Diastolic dysfunction may serve as a more sensitive tool for the early detection of cardiac damage and should be incorporated as a routine parameter in the functional monitoring of cardiotoxicity.

Impact of residual and intrafractional errors on strategy of correction for image-guided accelerated partial breast irradiation.

BACKGROUND: The cone beam CT (CBCT) guided radiation can reduce the systematic and random setup errors as compared to the skin-mark setup. However, the residual and intrafractional (RAIF) errors are still unknown. The purpose of this paper is to investigate the magnitude of RAIF errors and correction action levels needed in cone beam computed tomography (CBCT) guided accelerated partial breast irradiation (APBI). METHODS: Ten patients were enrolled in the prospective study of CBCT guided APBI. The postoperative tumor bed was irradiated with 38.5 Gy in 10 fractions over 5 days. Two cone-beam CT data sets were obtained with one before and one after the treatment delivery. The CBCT images were registered online to the planning CT images using the automatic algorithm followed by a fine manual adjustment. An action level of 3 mm, meaning that corrections were performed for translations exceeding 3 mm, was implemented in clinical treatments. Based on the acquired data, different correction action levels were simulated, and random RAIF errors, systematic RAIF errors and related margins before and after the treatments were determined for varying correction action levels. RESULTS: A total of 75 pairs of CBCT data sets were analyzed. The systematic and random setup errors based on skin-mark setup prior to treatment delivery were 2.1 mm and 1.8 mm in the lateral (LR), 3.1 mm and 2.3 mm in the superior-inferior (SI), and 2.3 mm and 2.0 mm in the anterior-posterior (AP) directions. With the 3 mm correction action level, the systematic and random RAIF errors were 2.5 mm and 2.3 mm in the LR direction, 2.3 mm and 2.3 mm in the SI direction, and 2.3 mm and 2.2 mm in the AP direction after treatments delivery. Accordingly, the margins for correction action levels of 3 mm, 4 mm, 5 mm, 6 mm and no correction were 7.9 mm, 8.0 mm, 8.0 mm, 7.9 mm and 8.0 mm in the LR direction; 6.4 mm, 7.1 mm, 7.9 mm, 9.2 mm and 10.5 mm in the SI direction; 7.6 mm, 7.9 mm, 9.4 mm, 10.1 mm and 12.7 mm in the AP direction, respectively. CONCLUSIONS: Residual and intrafractional errors can significantly affect the accuracy of image-guided APBI with nonplanar 3DCRT techniques. If a 10-mm CTV-PTV margin is applied, a correction action level of 5 mm or less is necessary so as to maintain the RAIF errors within 10 mm for more than 95% of fractions. Pre-treatment CBCT guidance is not a guarantee for safe delivery of the treatment despite its known benefits of reducing the initial setup errors. A patient position verification and correction during the treatment may be a method for the safe delivery.