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1.  Clinical practice guidelines for the care and treatment of breast cancer: 16. Locoregional post-mastectomy radiotherapy 
To provide information and recommendations to assist women with breast cancer and their physicians in making decisions regarding the use of locoregional post-mastectomy radiotherapy (PMRT).
Locoregional control, disease-free survival, overall survival and treatment-related toxicities.
This guideline is based on a review of all meta-analyses, consensus statements and other guidelines published between 1966 and November 2002. Searches of MEDLINE and CANCERLIT for English-language randomized controlled trials published between 1995 and November 2002 were also conducted to supplement the literature previously reviewed by the American Society of Clinical Oncology (ASCO) Health Services Research Committee panel in its published guideline. A nonsystematic review of the literature was continued through June 2003.
RecommendationsLocoregional PMRT is recommended for women with an advanced primary tumour (tumour size 5 cm or greater, or tumour invasion of the skin, pectoral muscle or chest wall).Locoregional PMRT is recommended for women with 4 or more positive axillary lymph nodes.The role of PMRT in women with 1 to 3 positive axillary lymph nodes is unclear. These women should be offered the opportunity to participate in clinical trials of PMRT.Locoregional PMRT is generally not recommended for women who have tumours that are less than 5 cm in diameter and who have negative axillary nodes.Other patient, tumour and treatment characteristics, including age, histologic grade, lymphovascular invasion, hormone receptor status, number of axillary nodes removed, axillary extracapsular extension and surgical margin status, may affect locoregional control, but their use in specifying additional indications for PMRT is currently unclear.PMRT should encompass the chest wall and the supraclavicular, infraclavicular and axillary apical lymph node areas.To reduce the risk of lymphedema, radiation of the entire axilla should not be used routinely after complete axillary dissection of level I and II lymph nodes.A definite recommendation regarding the inclusion of the internal mammary lymph nodes in PMRT cannot be made because of limited and inconsistent data.The use of modern techniques in radiotherapy planning is recommended to minimize excessive normal tissue exposure, particularly to the cardiac and pulmonary structures.Common short-term side effects of PMRT, including fatigue and skin erythema, are generally tolerable and not dose-limiting. Severe long-term side effects, including lymphedema, cardiac and pulmonary toxicities, brachial plexopathy, rib fractures and secondary neoplasms, are relatively rare.The optimal sequencing of PMRT and systemic therapy is currently unclear. Regimens containing anthracyclines or taxanes should not be administered concurrently with radiotherapy because of the potential for increased toxicity.
The authors' original text was submitted for review, revision and approval by the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Subsequently, feedback was provided by 11 oncologists from across Canada. The final document was approved by the steering committee.
The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer was convened by Health Canada.
Completion date
November 2003.
PMCID: PMC385392  PMID: 15078851
2.  Effects of postmastectomy radiotherapy on prognosis in different tumor stages of breast cancer patients with positive axillary lymph nodes 
Cancer Biology & Medicine  2014;11(2):123-129.
To explore the effects of postmastectomy radiotherapy (PMRT) on the locoregional failure-free survival (LRFFS) and overall survival (OS) of breast cancer patients under different tumor stages and with one to three positive axillary lymph nodes (ALNs).
We conducted a retrospective review of 527 patients with one to three positive lymph nodes who underwent modified radical or partial mastectomy and axillary dissection from January 2000 to December 2002. The patients were divided into the T1-T2 N1 and T3-T4 N1 groups. The effects of PMRT on the LRFFS and OS of these two patient groups were analyzed using SPSS 19.0, Pearson’s χ2-test, Kaplan-Meier method, and Cox proportional hazard model.
For T1-T2 N1 patients, no statistical significance was observed in the effects of PMRT on LRFFS [hazard ratio (HR)=0.726; 95% confidence interval (CI): 0.233-2.265; P=0.582] and OS (HR=0.914; 95% CI: 0.478-1.745; P=0.784) of the general patients. Extracapsular extension (ECE) and high histological grade were the risk factors for LRFFS and OS with statistical significance in multivariate analysis. Stratification analysis showed that PMRT statistically improved the clinical outcomes in high-risk patients [ECE (+), LRFFS: P=0.026, OS: P=0.007; histological grade III, LRFFS: P<0.001, OS: P=0.007] but not in low-risk patients [ECE (–), LRFFS: P=0.987, OS: P=0.502; histological grade I-II, LRFFS: P=0.816, OS: P=0.296]. For T3-T4 N1 patients, PMRT effectively improved the local control (HR=0.089; 95% CI: 0.210-0.378; P=0.001) of the general patients, whereas no statistical effect was observed on OS (HR=1.251; 95% CI: 0.597-2.622; P=0.552). Absence of estrogen receptors and progesterone receptors (ER/PR) (–) was an independent risk factor. Further stratification analysis indicated a statistical difference in LRFFS and OS between the high-risk patients with ER/PR (–) receiving PMRT and not receiving PMRT [ER/PR (–), LRFFS: P=0.046, OS: P=0.039]. However, PMRT had a beneficial effect on the reduction of locoregional recurrence (LRR) but not in total mortality [ER/PR (+), LRFFS: P<0.001, OS: P= 0.695] in T3-T4 N1 patients with ER/PR (+) who received endocrine therapy.
PMRT could reduce ECE (+), histological grade III-related LRR, and total mortality of T1-T2 N1 patients. T3-T4 N1 patients with ER/PR (–) could benefit from PMRT by improving LRFFS and OS. However, PMRT could only reduce LRR but failed to improve OS for T3-T4 N1 patients with ER/PR (+) who received endocrine therapy.
PMCID: PMC4069797  PMID: 25009754
Breast cancer; positive lymph nodes; postmastectomy radiotherapy (PMRT); locoregional failure-free survival (LRFFS); overall survival (OS)
3.  Postmastectomy Radiotherapy for Breast Cancer 
Cancer  2009;115(6):1185-1193.
Given accumulating evidence supporting postmastectomy radiotherapy (PMRT) in selected patients, it is important to evaluate patterns and correlates of PMRT utilization, including communication and attitudinal factors.
The authors surveyed 2382 patients diagnosed with breast cancer in 2002 and reported to the Los Angeles and Detroit Surveillance, Epidemiology, and End Results registries (n = 1844, 77.4% response rate). Analyses were restricted to patients with nonmetastatic invasive breast cancer treated by mastectomy who had decided whether or not to undergo PMRT (n = 396). The authors assessed rates of explanation, recommendation, and receipt of radiation by indication grouping, defined primarily by the 2001 American Society of Clinical Oncology guidelines. They evaluated correlates of PMRT receipt, including tumor and sociodemographic characteristics. They also explored patients’ self-reported reasons for nonreceipt of PMRT.
The adjusted proportion in each indication group reporting that a provider had explained radiation was high (77% of those in whom PMRT was indicated, 76% of those in whom medical opinion was divided, and 73% of those in whom PMRT was not indicated; P = .10). The adjusted proportions reporting recommendations for radiation (86%, 35%, and 17%, respectively) and receipt (81%, 34%, and 10%, respectively) varied significantly by indication grouping (P < .001). On multivariate analysis, tumor size (P < .001), lymph node status (P < .001), comorbidity (P = .02), and chemotherapy receipt (P = .003) were found to be independent significant correlates of PMRT receipt. The most common reasons cited for not pursuing PMRT were lack of physician recommendation and perceived lack of need.
PMRT receipt is strongly correlated with clinical indication. The authors found no sociodemographic disparities in utilization. However, approximately one-fifth of patients with strong indications did not receive treatment.
PMCID: PMC3905748  PMID: 19180636
mastectomy; radiotherapy; breast neoplasms; guideline adherence; quality of healthcare
4.  Post-Mastectomy Radiotherapy for Breast Cancer Patients with T1-T2 and 1-3 Positive Lymph Nodes: a Meta-Analysis 
PLoS ONE  2013;8(12):e81765.
The role of post-mastectomy radiotherapy (PMRT) in patients with T1-2 and 1-3 positive lymph nodes remains controversial. The aim of this study is to investigate the possible benefits of PMRT for this subgroup.
Three electronic databases were systematically quarried (Cochrane Library, MEDLINE, and EMBASE) for published studies evaluating the effects of PMRT on breast cancer patients with T1-T2 tumors with 1-3 positive lymph nodes. Of the 334 studies identified, information was available for 3432 patients from 10 clinical studies. Pooled relative risk estimates (RR) and overall survival (OS) were calculated using the inverse variance weighted approach, publication bias and chi-square test were also calculated.
From the 10 studies, the pooled RR (RRs) for locoregional recurrence (LRR) with PMRT was 0.348 (95% CI = 0.254 to 0.477), suggesting a significant benefit for PMRT to decrease the risk of LRR in patients with T1-T2 tumors and 1-3 positive nodes (p<0.05). Reporting bias ( Begg’s p = 0.152; Egger’s p = 0.107) or significant heterogeneity (Cochran’s p = 0.380; I2 = 6.7%) were not detected. For further subset analysis, the RR for T1, N1-3+ tumors was 0.330 (95% CI = 0.171 to 0.639); for T2, N1-3+ tumors the RR was 0.226 (95% CI = 0.121 to 0.424). The pooled RR for overall survival (OS) was not significantly different between PMRT and no-PMRT group (1.051, 95% CI =1.001 to 1.104).
Our pooled analysis revealed that PMRT significantly reduces the risk of LRR in patients with TI-T2 tumors with 1-3 positive nodes, and the magnitude of the LRR risk reduction is slightly greater for larger tumors. Our results suggest that PMRT should be considered for patients with T1/T2 tumors with 1-3 positive nodes to decrease the relatively high risk of LRR.
PMCID: PMC3849378  PMID: 24312582
5.  Real-world outcomes of postmastectomy radiotherapy in breast cancer patients with 1–3 positive lymph nodes: a retrospective study 
Journal of Radiation Research  2013;55(1):121-128.
Objective: To assess the treatment outcomes and to explore the determinants of clinical outcome in breast cancer patients with 1–3 positive nodes who did or did not receive postmastectomy radiotherapy (PMRT) in a tertiary care referral cancer center in Northern Thailand. Methods: We investigated a retrospective cohort of registered breast cancer patients at the Faculty of Medicine, Chiang Mai University, Thailand from 2001–2007. Analysis was performed using Cox regression models to identify factors affecting the overall survival (OS) and relapse-free survival (RFS) rates. Comparisons were made between two cohorts: women who received adjuvant PMRT (74 patients) and women who did not receive adjuvant PMRT (81 patients). Results: A total of 155 patients were included with a median follow-up period of 4.45 years. There was a statistically significant 4-year OS difference between the two groups of patients: 100% for the PMRT group and 93.1% for the non-PMRT group (P = 0.044). The 4-year RFS was 85.9% for patients receiving PMRT and 78.3% for patients who did not receive PMRT (P = 0.291). On multivariate analysis of OS, using hormonal treatment was the only significant independent factor associated with improved OS. On multivariate analysis of RFS, none of the variables were significantly associated with improved RFS. PMRT was notfound to be a prognostic variable related to the outcome of patients using a logistic regression model. Conclusion: Our retrospective, hospital-based analysis demonstrated that PMRT improved the treatment outcome in terms of OS for women with 1–3 node positive early-stage breast cancer.
PMCID: PMC3885117  PMID: 23788495
postmastectomy radiotherapy; 1–3 positive nodes; breast cancer; Thai
6.  Non-compliance with a postmastectomy radiotherapy guideline: Decision tree and cause analysis 
The guideline for postmastectomy radiotherapy (PMRT), which is prescribed to reduce recurrence of breast cancer in the chest wall and improve overall survival, is not always followed. Identifying and extracting important patterns of non-compliance are crucial in maintaining the quality of care in Oncology.
Analysis of 759 patients with malignant breast cancer using decision tree induction (DTI) found patterns of non-compliance with the guideline. The PMRT guideline was used to separate cases according to the recommendation to receive or not receive PMRT. The two groups of patients were analyzed separately. Resulting patterns were transformed into rules that were then compared with the reasons that were extracted by manual inspection of records for the non-compliant cases.
Analyzing patients in the group who should receive PMRT according to the guideline did not result in a robust decision tree. However, classification of the other group, patients who should not receive PMRT treatment according to the guideline, resulted in a tree with nine leaves and three of them were representing non-compliance with the guideline. In a comparison between rules resulting from these three non-compliant patterns and manual inspection of patient records, the following was found:
In the decision tree, presence of perigland growth is the most important variable followed by number of malignantly invaded lymph nodes and level of Progesterone receptor. DNA index, age, size of the tumor and level of Estrogen receptor are also involved but with less importance. From manual inspection of the cases, the most frequent pattern for non-compliance is age above the threshold followed by near cut-off values for risk factors and unknown reasons.
Comparison of patterns of non-compliance acquired from data mining and manual inspection of patient records demonstrates that not all of the non-compliances are repetitive or important. There are some overlaps between important variables acquired from manual inspection of patient records and data mining but they are not identical. Data mining can highlight non-compliance patterns valuable for guideline authors and for medical audit. Improving guidelines by using feedback from data mining can improve the quality of care in oncology.
PMCID: PMC2556998  PMID: 18803875
7.  Which Patients Might Benefit from Postmastectomy Radiotherapy in Breast Cancer Patients with T1-2 Tumor and 1-3 Axillary Lymph Nodes Metastasis? 
This study compared the clinical outcomes of T1-2N1 breast cancer patients with and without postmastectomy radiotherapy (PMRT). Risk factors for loco-regional recurrence (LRR) were identified in order to define a subgroup of patients who might benefit from PMRT.
Materials and Methods
Of 110 T1-2N1 breast cancer patients who underwent mastectomy from January 1994 through December 2009, 32 patients underwent PMRT and 78 patients did not. Treatment outcomes and risk factors for LRR were analyzed.
The 5- and 10-year LRR rates were both 6.2% in the PMRT group, and 10.4% and 14.6% in the no-PMRT group (p=0.336). In addition, no significant differences in distant metastasis-free survival (DMFS) or overall survival (OS) were observed between patients receiving and not receiving PMRT. In multivariate analysis, factors associated with higher LRR rates included grade 3 disease, extracapsular extension (ECE), and triple negative subtype. Patients who had one or more risk factors for LRR were defined as a high-risk patient group. In the high-risk group, both 5- and 10-year LRR rates for patients who underwent PMRT was 18.2%, and LRR rates of 21.4% at five years and 36.6% at 10 years were observed for patients who did not undergo PMRT (p=0.069).
PMRT in T1-2N1 breast cancer patients should be considered according to several prognostic factors in addition to T and N stage. Findings of our study indicated that PMRT did not improve LRR, DMFS, or OS in T1-2N1 breast cancer patients. However, in a subgroup of patients with grade 3 disease, ECE, or triple negative subtype, PMRT might be beneficial.
PMCID: PMC3710959  PMID: 23864843
Breast neoplasms; Radiotherapy; Mastectomy; Risk factor
Postmastectomy radiation therapy (PMRT) can reduce locoregional recurrences (LRR) in high-risk patients, but its role in the treatment of lymph node negative (LN−) breast cancer remains unclear. The aim of this study was to identify a subgroup of T1-T2 breast cancer patients with LN− who might benefit from PMRT.
Methods and Materials
We retrospectively reviewed 1,136 node-negative T1-T2 breast cancer cases treated with mastectomy without PMRT at the Massachusetts General Hospital between 1980 and 2004. We estimated cumulative incidence rates for LRR overall and in specific subgroups, and used Cox proportional hazards models to identify potential risk factors.
Median follow-up was 9 years. The 10-year cumulative incidence of LRR was 5.2% (95% CI: 3.9–6.7%). Chest wall was the most common (73%) site of LRR. Tumor size, margin, patient age, systemic therapy, and lymphovascular invasion (LVI) were significantly associated with LRR on multivariate analysis. These five variables were subsequently used as risk factors for stratified analysis. The 10-year cumulative incidence of LRR for patients with no risk factors was 2.0% (95% CI: 0.5–5.2%), whereas the incidence for patients with three or more risk factors was 19.7% (95% CI: 12.2–28.6%).
It has been suggested that patients with T1-T2N0 breast cancer who undergo mastectomy represent a favorable group for which PMRT renders little benefit. However, this study suggests that select patients with multiple risk factors including LVI, tumor size ≥2 cm, close or positive margin, age ≤50, and no systemic therapy are at higher risk of LRR and may benefit from PMRT.
PMCID: PMC3722592  PMID: 21420245
Breast cancer; Mastectomy; Postmastectomy radiation; Risk factors; Locoregional recurrence
9.  Radiotherapy Can Improve the Disease-Free Survival Rate in Triple-Negative Breast Cancer Patients with T1–T2 Disease and One to Three Positive Lymph Nodes After Mastectomy 
The Oncologist  2013;18(2):141-147.
The impact of postmastectomy radiotherapy (PMRT) on locoregional recurrence–free survival (LRFS) and disease-free survival (DFS) outcomes was investigated in patients with triple-negative breast cancer. PMRT was associated with longer LRFS and DFS times in high-risk TNBC patients and a longer DFS time in intermediate-risk TNBC patients.
Learning Objectives
Evaluate the effect of postmastectomy radiotherapy (PMRT) in terms of locoregional recurrence-free survival and disease-free survival in triple-negative breast cancer (TNBC) patients.Identify the subgroup of TNBC patients most likely to benefit from PMRT.Assess the role of PMRT in TNBC patients with intermediate-risk (T1/2N1) disease.
Several studies have demonstrated poor locoregional control in patients with triple-negative breast cancer (TNBC), compared with other molecular subtypes of breast cancer. We sought to evaluate whether or not postmastectomy radiotherapy (PMRT) improves locoregional recurrence-free survival (LRFS) and disease-free survival (DFS) outcomes in TNBC patients.
Methods and Materials.
Between January 2000 and July 2007, 553 TNBC patients treated with modified radical mastectomy from a single institution were analyzed retrospectively. Patients were categorized into three groups: low risk (stage T1–T2N0), intermediate risk (stage T1–T2N1), and high risk (stage T3–T4 and/or N2–N3). Cox proportional hazards models were used to evaluate the association between PMRT and LRFS and DFS times after adjusting for other clinicopathologic covariates.
With a median follow-up of 65 months (range, 1–140 months), 51 patients (9.2%) developed locoregional recurrence and 135 patients (24.4%) experienced disease recurrence. On multivariate analysis, PMRT was associated with significantly longer LRFS and DFS times in the entire cohort. In the intermediate-risk group, PMRT was associated with a longer DFS time but not with the LRFS interval. In the high-risk group, PMRT was associated with significantly longer LRFS and DFS times.
PMRT is associated with longer LRFS and DFS times in high-risk TNBC patients and a longer DFS time in intermediate-risk TNBC patients. Prospective randomized studies are needed to investigate the best locoregional treatment approaches for patients with this molecular subtype of breast cancer.
PMCID: PMC3579597  PMID: 23335622
Breast cancer; Triple negative; Postmastectomy radiotherapy; Locoregional recurrence; Disease-free survival
10.  Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report 
Annals of Oncology  2012;23(11):2852-2858.
Rates and risk factors of local, axillary and supraclavicular recurrences can guide patient selection and target for postmastectomy radiotherapy (PMRT).
Patients and methods
Local, axillary and supraclavicular recurrences were evaluated in 8106 patients enrolled in 13 randomized trials. Patients received chemotherapy and/or endocrine therapy and mastectomy without radiotherapy. Median follow-up was 15.2 years.
Ten-year cumulative incidence for chest wall recurrence of >15% was seen in patients aged <40 years (16.1%), with ≥4 positive nodes (16.5%) or 0–7 uninvolved nodes (15.1%); for supraclavicular failures >10%: ≥4 positive nodes (10.2%); for axillary failures of >5%: aged <40 years (5.1%), unknown primary tumor size (5.2%), 0–7 uninvolved nodes (5.2%). In patients with 1–3 positive nodes, 10-year cumulative incidence for chest wall recurrence of >15% were age <40, peritumoral vessel invasion or 0–7 uninvolved nodes. Age, number of positive nodes and number of uninvolved nodes were significant parameters for each locoregional relapse site.
PMRT to the chest wall and supraclavicular fossa is supported in patients with ≥4 positive nodes. With 1–3 positive nodes, chest wall PMRT may be considered in patients aged <40 years, with 0–7 uninvolved nodes or with vascular invasion. The findings do not support PMRT to the dissected axilla.
PMCID: PMC3477880  PMID: 22776708
adjuvant treatment; breast cancer; locoregional recurrence; postmastectomy radiotherapy
11.  Postmastectomy irradiation in breast in breast cancer patients with T1-2 and 1-3 positive axillary lymph nodes: Is there a role for radiation therapy? 
We aimed to evaluate retrospectively the correlation of loco-regional relapse (LRR) rate, distant metastasis (DM) rate, disease free survival (DFS) and overall survival (OS) in a group of breast cancer (BC) patients who are at intermediate risk for LRR (T1-2 tumor and 1-3 positive axillary nodes) treated with or without postmastectomy radiotherapy (PMRT) following modified radical mastectomy (MRM).
Ninety patients, with T1-T2 tumor, and 1-3 positive nodes who had undergone MRM received adjuvant systemic therapy with (n = 66) or without (n = 24) PMRT. Patient-related characteristics (age, menopausal status, pathological stage/tumor size, tumor location, histology, estrogen/progesterone receptor status, histological grade, nuclear grade, extracapsular extension, lymphatic, vascular and perineural invasion and ratio of involved nodes/dissected nodes) and treatment-related factors (PMRT, chemotherapy and hormonal therapy) were evaluated in terms of LRR and DM rate. The 5-year Kaplan-Meier DFS and OS rates were analysed.
Differences between RT and no-RT groups were statistically significant for all comparisons in favor of RT group except OS: LRR rate (3%vs 17%, p = 0.038), DM rate (12% vs 42%, p = 0.004), 5 year DFS (82.4% vs 52.4%, p = 0.034), 5 year OS (90,2% vs 61,9%, p = 0.087). In multivariate analysis DM and lymphatic invasion were independent poor prognostic factors for OS.
PMRT for T1-2, N1-3 positive BC patients has to be reconsidered according to the prognostic factors and the decision has to be made individually with the consideration of long-term morbidity and with the patient approval.
PMCID: PMC3072917  PMID: 21450076
12.  No difference in dose distribution in organs at risk in postmastectomy radiotherapy with or without breast implant reconstruction 
The aim of this study was to quantify the variation in doses to organs at risk (ipsilateral lung and heart) and the clinical target volume (CTV) in the presence of breast implants. In this retrospective cohort study, patients were identified through the National Breast Cancer Register. Consecutive breast cancer patients undergoing mastectomy between 2009 and 2011 and completing a full course of postmastectomy radiotherapy (PMRT) were eligible. All included patients (n = 818) were identified in the ARIA© oncology information system and further stratified for immediate breast reconstruction (IBR+, n = 162) and no immediate breast reconstruction (IBR-, n = 656). Dose statistics for ipsilateral lung, heart and CTV were retrieved from the system. Radiation plans for patients with chest wall (CW) only (n = 242) and CW plus lymph nodes (n = 576) irradiation were studied separately.
The outcome variables were dichotomized as follows: lung, V20Gy ≤ 30% vs. V20Gy > 30%; heart, Dmean ≤ 5 Gy vs. Dmean > 5 Gy; CTV, V95% ≥ median vs. V95% < median.
In the univariate and multivariate regression models no correlation between potential confounders (i.e. breast reconstruction, side of PMRT, CW index) and the outcome variables was found. Multivariate analysis of CW plus lymph nodes radiation plans, for example, showed no association of breast reconstruction with dosimetric outcomes in neither lung nor heart- lung V20Gy (odds ratio [OR]: 0.6, 95%CI, 0.4 to 1.0, p = 0.07) or heart Dmean (OR: 1.2, 95%CI, 0.5 to 3.1, p = 0.72), respectively.
CTV was statistically significantly larger in the IBR+ group (i.e. included breast implant), but no correlation between the implant type and dosimetric characteristics of the organs at risk was revealed.
In the current study, the presence of breast implants during postmastectomy radiotherapy was not associated with increased doses to ipsilateral lung and heart, but CTV definition and its dosimetric characteristics urge further evaluation.
PMCID: PMC3907145  PMID: 24406085
13.  Postmastectomy Radiotherapy for Locally Advanced Breast Cancer Receiving Neoadjuvant Chemotherapy 
BioMed Research International  2014;2014:719175.
Neoadjuvant chemotherapy (NAC) is widely used in locally advanced breast cancer (BC) treatment. The role of postmastectomy radiotherapy (PMRT) after NAC is strongly debated. The aim of our analysis was to identify major prognostic factors in a single-center series, with emphasis on PMRT. From 1997 to 2011, 170 patients were treated with NAC and mastectomy at our center; 98 cases (57.6%) underwent PMRT and 72 cases (42.4%) did not receive radiation. At a median follow-up period of 7.7 years (range 2–16) for the whole cohort, median time to locoregional recurrence (LRR) was 3.3 years (range 0.7–12.4). The 5-year and 10-year actuarial LRR rate were 14.5% and 15.9%, respectively. At the multivariate analysis the factors that significantly correlated with survival outcome were ≥4 positive nodes (HR 5.0, 1.51–16.52; P = 0.035), extracapsular extension (HR 2.18, 1.37–3.46; P = 0.009), and estrogen receptor positive disease (HR 0.57, 0.36–0.90; P = 0.003). Concerning LRR according to use of radiation, PMRT reduced LRR for patient with clinical T3 staged disease (P = 0.015). Our experience confirmed the impact of pathological nodal involvement on survival outcome. PMRT was found to improve local control in patients presenting with clinical T3 tumors, regardless of the response to chemotherapy.
PMCID: PMC4090568  PMID: 25045694
14.  Analysis of the Effects of Breast Reconstruction in Breast Cancer Patients Receiving Radiotherapy after Mastectomy 
Archives of Plastic Surgery  2012;39(3):222-226.
Immediate breast reconstruction after mastectomy and delayed breast reconstruction with post-supplementary treatment are the two types of breast reconstruction currently performed when treating breast cancer. Post-mastectomy radiation therapy (PMRT) not only reduces local recurrence but also improves overall survival. However, the complications and survival rates associated with PMRT need to be clear when determining the timing of breast reconstruction. Accordingly, we investigated the optimal timing of breast reconstruction by observing patients who underwent mastectomy followed by PMRT, based on their overall health and aesthetic satisfaction.
We retrospectively reviewed 21 patients who underwent breast reconstruction with PMRT between November 2004 and November 2010. We collected data regarding the various methods of mastectomy, and the modality of adjuvant therapy, such as chemotherapy, hormone therapy, and radiotherapy. Telephone interviews were conducted to study the general and aesthetic satisfaction.
Patients who received PMRT after breast reconstruction showed a greater complication rate than those undergoing breast reconstruction after PMRT (P=0.02). Aesthetic satisfaction was significantly higher in the groups undergoing breast reconstruction after PMRT (P=0.03). Patients who underwent breast reconstruction before PMRT developed complications more frequently, but they expressed greater aesthetic satisfaction with the treatment.
It is recommended that the complication rates and aesthetic satisfaction after breast reconstruction be carefully considered when determining the optimal timing for radiotherapy.
PMCID: PMC3385332  PMID: 22783530
Breast; Mastectomy; Radiotherapy
15.  Clinical relevance of lymph node ratio in breast cancer patients with one to three positive lymph nodes 
British Journal of Cancer  2013;109(5):1165-1171.
To test the hypotheses that breast cancer patients with one to three positive lymph nodes (pN1) consist of heterogeneous prognostic subsets and that the ratio of positive nodes to total nodes dissected (lymph node ratio, LNR) might discriminate patients with a higher risk as candidates for post-mastectomy radiation therapy (PMRT).
Using information from 7741 node-positive patients, we first identified cutoff values of the LNR using the nonparametric bootstrap method. Focusing on 3477 patients with pN1 disease, we then evaluated the clinical relevance of the LNR categorised by the estimated cutoff values (categorised LNR, cLNR).
Among 3477 patients with pN1 disease, 3059 and 418 patients were assigned into the low and intermediate cLNR groups, respectively, based on a cutoff value of 0.18. The prognostic factors associated with poor overall survival (OS) included younger age, T2 stage, negative oestrogen/progesterone receptors, high histologic grade, and intermediate cLNR. Post-mastectomy radiation therapy significantly increased OS in patients assigned to the intermediate cLNR (hazard ratio, 0.39; 95% confidence interval, 0.17–0.89; P=0.0248), whereas patients in the low cLNR group derived no additional survival benefit from PMRT.
This study suggests that PMRT should be recommended for patients with pN1 disease and an intermediate cLNR.
PMCID: PMC3778309  PMID: 23942073
breast neoplasms; lymph node ratio; pN1; prognostic factor; predictive factor; post-mastectomy radiation therapy
16.  Evaluation of volumetric modulated arc therapy for postmastectomy treatment 
To examine the feasibility of volumetric modulated arc therapy (VMAT) for post mastectomy radiotherapy (PMRT).
Methods and materials
Fifteen PMRT patients previously treated at our clinic with helical tomotherapy (HT) were identified for the study. Planning target volumes (PTV) included the chest wall and regional lymph nodes. A systematic approach to constructing VMAT that met the clinical goals was devised. VMAT plans were then constructed for each patient and compared with HT plans with which they had been treated. The resulting plans were compared on the basis of PTV coverage; dose homogeneity index (DHI) and conformity index (CI); dose to organs at risk (OAR); tumor control probability (TCP), normal tissue complication probability (NTCP) and secondary cancer complication probability (SCCP); and treatment delivery time. Differences were tested for significance using the paired Student’s t-test.
Both modalities produced clinically acceptable PMRT plans. VMAT plans showed better CI (p < 0.01) and better OAR sparing at low doses than HT plans, particularly at doses less than 5 Gy. On the other hand, HT plans showed better DHI (p < 0.01) and showed better OAR sparing at higher doses. Both modalities achieved nearly 100% tumor control probability and approximately 1% NTCP in the lungs and heart. VMAT showed lower SCCP than HT (p < 0.01), though both plans showed higher SCCP values than conventional mixed beam (electron-photon) plans reported by our group previously. VMAT plans required 66.2% less time to deliver than HT.
Both VMAT and HT provide acceptable treatment plans for PMRT. Both techniques are currently utilized at our institution.
PMCID: PMC3984750  PMID: 24571913
Volumetric modulated arc therapy; Helical tomotherapy; Post mastectomy
17.  Factors associated with guideline-concordant use of radiation therapy after mastectomy in the National Comprehensive Cancer Network 
We examined rates and determinants of appropriate and inappropriate use of post-mastectomy radiation (PMRT), as defined by NCCN practice guidelines, among women with Stage I-II breast cancer (AJCC 5th Edition).
Using clinical characteristics, 1,620 consecutive patients at eight NCCN institutions who received mastectomy between 7/97–6/02 were classified into three cohorts according to whether guidelines (1) recommended PMRT, (2) recommended against PMRT, or (3) made no definitive PMRT recommendation. We defined the absence of PMRT in the first cohort as underuse, and receipt of PMRT in the second cohort as overuse. Multivariable logistic regression was applied to investigate the association of clinical and sociodemographic factors with PMRT.
Overall, 23.8% received PMRT. This included 83.6% (199/238) in the “recommend PMRT” cohort, 5.6% (58/1029) in the “recommend against PMRT” cohort, and 38.6% (127/329) in the “consider PMRT” cohort. The only factor associated with underuse in the “recommend PMRT” cohort was not receiving chemotherapy (OR=0.08, p<0.0001). In addition to tumor characteristics, factors associated with overuse in the “recommend against PMRT ” cohort included age<50 (OR=2.28, p=0.048), NCCN institution (OR=1.04–8.29, p=0.026), higher education (OR=1.25–9.01, p=0.001), and no reconstructive surgery (OR=2.44, p=0.019). Factors associated with PMRT in the “consider PMRT” cohort included NCCN institution (OR=3.8–9.01, p<0.0001), age<50 (OR=2.26, p=0.041) and tumor characteristics.
Concordance with definitive treatment guidelines was high. However, when current evidence does not support a definitive recommendation for PMRT, treatment decisions appear to be influenced not only by patient age and clinical characteristics, but also by institution-specific patterns of care.
PMCID: PMC2730025  PMID: 18472360
Breast cancer; guideline adherence; mastectomy; quality of health care
18.  Dose to level I and II axillary lymph nodes and lung by tangential field radiation in patients undergoing postmastectomy radiation with tissue expander reconstruction 
To define the dosimetric coverage of level I/II axillary volumes and the lung volume irradiated in postmastectomy radiotherapy (PMRT) following tissue expander placement.
Methods and Materials
Twenty-three patients were identified who had undergone postmastectomy radiotherapy with tangent only fields. All patients had pre-radiation tissue expander placement and expansion. Thirteen patients had bilateral expander reconstruction. The level I/II axillary volumes were contoured using the RTOG contouring atlas. The patient-specific variables of expander volume, superior-to-inferior location of expander, distance between expanders, expander angle and axillary volume were analyzed to determine their relationship to the axillary volume and lung volume dose.
The mean coverage of the level I/II axillary volume by the 95% isodose line (VD95%) was 23.9% (range 0.3 - 65.4%). The mean Ipsilateral Lung VD50% was 8.8% (2.2-20.9). Ipsilateral and contralateral expander volume correlated to Axillary VD95% in patients with bilateral reconstruction (p = 0.01 and 0.006, respectively) but not those with ipsilateral only reconstruction (p = 0.60). Ipsilateral Lung VD50% correlated with angle of the expander from midline (p = 0.05).
In patients undergoing PMRT with tissue expanders, incidental doses delivered by tangents to the axilla, as defined by the RTOG contouring atlas, do not provide adequate coverage. The posterior-superior region of level I and II is the region most commonly underdosed. Axillary volume coverage increased with increasing expander volumes in patients with bilateral reconstruction. Lung dose increased with increasing expander angle from midline. This information should be considered both when placing expanders and when designing PMRT tangent only treatment plans by contouring and targeting the axilla volume when axillary treatment is indicated.
PMCID: PMC3267695  PMID: 22204504
post-mastectomy radiation; axillary dose; tissue expander; breast reconstruction; tangent fields
19.  Axillary treatment for patients with early breast cancer and lymph node metastasis: systematic review protocol 
For patients with early breast cancer and lymph node metastasis, axillary treatment is widely recommended. This is either surgical removal of the axillary lymph nodes, or axillary radiotherapy. The rationale for axillary treatment is that it will reduce the risk of recurrence in the axilla, and may improve survival. However, both treatments are associated with adverse effects, such as lymphedema, pain and sensory loss, and are costly to the health services and to patients. With improvements in adjuvant therapy, routine axillary treatment may no longer offer any overall advantage.
To assess the short and long term benefits and adverse effects of routine axillary treatment (axillary lymph node clearance or axillary radiotherapy) for patients with lymph node positive early-stage breast cancer.
Criteria for potentially eligibility for the study will be that the participants are men and women with early breast cancer and lymph nodes with metastasis. The study compares either axillary treatment with no axillary treatment, or axillary node clearance with axillary radiotherapy, and the study is a randomized trial. Primary outcomes are axillary recurrence, disease-free and overall survival. Secondary outcomes include breast or chest wall recurrence, distant metastasis, time to axillary recurrence, axillary recurrence-free survival, arm morbidity, quality of life and health economic costs. The search strategy will include the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and WHO International Clinical Trials Registry Platform (ICTRP) search portal. Two independent reviewers will assess studies for inclusion in the review, assess study quality and extract data. Characteristics of included studies will be described. Meta-analysis will be conducted using ReVman software.
This review addresses an important clinical question, and results will inform clinical practice and health care policy.
PMCID: PMC3562161  PMID: 23317390
20.  The effects of ECE on the benefits of PMRT for breast cancer patients with positive axillary nodes 
Journal of Radiation Research  2013;54(4):712-718.
The purpose of the present study was to retrospectively evaluate the effects of extracapsular extension (ECE) on the benefits of post-mastectomy radiation therapy (PMRT) for groups of patients with varying numbers of positive axillary nodes (1–3, 4–9 and ≥10 positive axillary nodes). Methods: A total of 1220 axillary node-positive patients who had received mastectomy were involved in this study. Patients were grouped as ‘Radio + /ECE + ’, ‘Radio–/ECE + ’, ‘Radio + /ECE–’ or ‘Radio–/ECE–’ according to status of ECE and whether receiving PMRT or not, and were evaluated in terms of local region relapse (LRR) rate. The 5-year and 10-year Kaplan-Meier disease-free survival and overall survival (OS) rates were analyzed. Results: ECE-positive differed from ECE-negative groups with statistical significance for all comparisons in favor of the ECE-negative group: 5-year locoregional failure-free survival (LRFFS) (82.69% vs 91.83%, P < 0.001), 10-year LRFFS (75.39% vs 90.02%, P < 0.001); 5-year OS (52.12% vs 74.46%, P < 0.001), 10-year OS (35.17% vs 67.63%, P < 0.001). There were no significant effects of ECE on the benefits of PMRT for patients with 1–3 (P = 0.5720), ≥10(P = 0.0614) positive axillary nodes. However, for the group of patients with 4–9 positive axillary nodes, ECE status had a significant effect on the benefits of PMRT with respect to 5-year and 10-year LRFFS (P < 0.05). Conclusion: In our study, regardless of the ECE status, PMRT didn't significantly improve the LRFFS for patients with 1–3 or ≥10 positive axillary nodes. However, for patients with 4–9 positive axillary nodes, ECE could be an important criterion to consider when deciding whether to receive PMRT.
PMCID: PMC3709674  PMID: 23392824
breast neoplasms; ECE; PMRT; prognosis
21.  Results of the First Austrian Multidisciplinary Expert Panel on Controversies in Local Treatment of Breast Cancer 
Breast Care  2012;7(1):61-66.
At the first Austrian multidisciplinary expert panel on controversies in local treatment of breast cancer, 22 experts of all relevant disciplines discussed current areas of debate (surgery of the breast, surgery and pathology of the axilla, reconstructive surgery, radiotherapy, and imaging) in local therapy. The most controversial area of debate was the area of axillary surgery. The panel agreed that it was no longer necessary to perform completion axillary lymph node dissection (ALND) when micrometastases are diagnosed in the sentinel lymph node. The only prospective trial comparing patients with sentinel node macrometastases with or without completion ALND had to be terminated early due to failure in sufficient patient recruitment. As long as the frequently discussed issues have not been solved and in light of the lack of any clear level 1 evidence, the panel decided not to recommend omitting axillary dissection in patients with 1 or 2 macrometastases meeting the inclusion criteria of the ACOSOG Z0011 trial. The Austrian panel similarly decided not to recommend omitting axillary dissection in patients with macrometastases and low-risk breast cancer in general. These decisions reflect the increasing skepticism of the scientific community against rapidly shifting paradigms without sufficient and clear evidence.
PMCID: PMC3335360  PMID: 22553475
Breast cancer: local therapy, surgery, radiotherapy; Expert panel
22.  Radiation treatment for breast cancer. Recent advances. 
Canadian Family Physician  2002;48:1065-1069.
OBJECTIVE: To review recent advances in radiation therapy in treatment of breast cancer. QUALITY OF EVIDENCE: MEDLINE and CANCERLIT were searched using the MeSH words breast cancer, ductal carcinoma in situ, sentinel lymph node biopsy, and postmastectomy radiation. Randomized studies have shown the efficacy of radiation treatment for ductal carcinoma in situ (DCIS) and for invasive breast cancer. MAIN MESSAGE: Lumpectomy followed by radiation is effective treatment for DCIS. In early breast cancer, shorter radiation schedules are as efficacious for local control and short-term cosmetic results as traditional fractionation regimens. Sentinel lymph node biopsy is done in specialized cancer centres; regional radiation is recommended for patients with four or more positive axillary lymph nodes. Postmastectomy radiation has been shown to have survival benefits for high-risk premenopausal patients. Systemic metastases from breast cancer usually respond satisfactorily to radiation. CONCLUSION: Radiation therapy continues to have an important role in treatment of breast cancer. There have been great advances in radiation therapy in the last decade, but they have raised controversy. Further studies are needed to address the controversies.
PMCID: PMC2214065  PMID: 12113193
23.  Prognostic Value of the Nodal Ratio and Ki-67 Expression in Breast Cancer Patients Treated with Postmastectomy Radiotherapy 
Journal of Breast Cancer  2013;16(3):274-284.
This pilot study aimed to evaluate prognostic factors of postmastectomy radiotherapy (PMRT) for breast cancer patients undergoing systemic therapy in either preoperative or postoperative setting.
Between 2003 and 2009, 113 patients received PMRT: 61 underwent preoperative systemic therapy (PST subgroup) and 52 received postoperative systemic therapy (non-PST subgroup).
The median follow-up time was 72.3 months (range, 34.0-109.4 months) for surviving patients. In univariate analysis of all patients, disease-free survival (DFS) was associated with age, nodal ratio (NR), and Ki-67 expression; overall survival (OS) was associated with NR and Ki-67 expression. Pathologic N stage and HER2 expression were marginally associated with DFS and OS. In the non-PST subgroup, DFS was associated with age, NR, venous invasion, and Ki-67 expression; OS was associated with age. In the PST subgroup, DFS was associated with ypN stage and NR; OS was associated with ypN, histologic grade, HER2 expression, and p53 expression. In multivariate analysis of all patients, DFS and OS were significantly associated with NR (p=0.003 and p=0.019, respectively) and Ki-67 expression (p=0.002 and p=0.015, respectively). Patients were classified into low-risk (NR ≤0.2 and Ki-67 ≤20%; n=34), intermediate-risk (NR >0.2 or Ki-67 >20%; n=63), and high-risk (NR >0.2 and Ki-67 >20%; n=16) subgroups. All low-risk patients were alive at the time of analysis. High-risk (p<0.001 and p=0.001, respectively) and intermediate-risk (p=0.022 and p=0.008, respectively) patients had significantly shorter DFS and OS than low-risk patients. This prognostic model was statistically significant for DFS when applied to the PST (p=0.001) and non-PST (p=0.016) subgroups separately.
For breast cancer patients undergoing PMRT, NR and Ki-67 are potential prognostic factors. A model using these factors might help predict a poor prognosis. Whether NR and Ki-67 are also prognostic for different setting of systemic therapy, preoperative or postoperative, warrants further study.
PMCID: PMC3800723  PMID: 24155756
Breast neoplasms; Ki-67 antigen; Lymph nodes; Mastectomy; Radiotherapy
24.  Non–Sentinel Lymph Node Metastases Associated With Isolated Breast Cancer Cells in the Sentinel Node 
There are many reports on the frequency of non–sentinel lymph node involvement when isolated tumor cells are found in the sentinel node, but results and recommendations for the use of an axillary lymph node dissection differ among studies. This systematic review was conducted to give an overview of this issue and to provide recommendations for the use of an axillary lymph node dissection in these patients. We searched Medline, Embase, and Cochrane databases from January 1, 2002, through November 27, 2007, for articles on patients with invasive breast cancer who had isolated tumor cells in the sentinel lymph node (according to the sixth edition of the Cancer Staging Manual of the American Joint Committee on Cancer) and who also underwent axillary lymph node dissection. Of 411 selected articles, 29 (including 836 patients) were included in this review. These 29 studies were heterogeneous, reporting a wide range of non–sentinel lymph node involvement (defined as the presence of isolated tumor cells or micro- or macrometastases) associated with isolated tumor cells in the sentinel lymph node, with an overall pooled risk for such involvement of 12.3% (95% confidence interval = 9.5% to 15.7%). This pooled risk estimate was marginally higher than the risk of a false-negative sentinel lymph node biopsy examination (ie, 7%–8%) but marginally lower than the risk of non–sentinel lymph node metastases in patients with micrometastases (ie, approximately 20%) who are currently eligible for an axillary lymph node dissection. Because 36 (64%) of the 56 patients with isolated tumor cells in their sentinel lymph node also had non–sentinel lymph node macrometastases, those patients with isolated tumor cells in the sentinel lymph node without other indications for adjuvant systemic therapy might be candidates for axillary lymph node dissection.
PMCID: PMC3299206  PMID: 19001602
25.  Proton radiotherapy for chest wall and regional lymphatic radiation; dose comparisons and treatment delivery 
The delivery of post-mastectomy radiation therapy (PMRT) can be challenging for patients with left sided breast cancer that have undergone mastectomy. This study investigates the use of protons for PMRT in selected patients with unfavorable cardiac anatomy. We also report the first clinical application of protons for these patients.
Methods and materials
Eleven patients were planned with protons, partially wide tangent photon fields (PWTF), and photon/electron (P/E) fields. Plans were generated with the goal of achieving 95% coverage of target volumes while maximally sparing cardiac and pulmonary structures. In addition, we report on two patients with unfavorable cardiac anatomy and IMN involvement that were treated with a mix of proton and standard radiation.
PWTF, P/E, and proton plans were generated and compared. Reasonable target volume coverage was achieved with PWTF and P/E fields, but proton therapy achieved superior coverage with a more homogeneous plan. Substantial cardiac and pulmonary sparing was achieved with proton therapy as compared to PWTF and P/E. In the two clinical cases, the delivery of proton radiation with a 7.2 to 9 Gy photon and electron component was feasible and well tolerated. Akimbo positioning was necessary for gantry clearance for one patient; the other was treated on a breast board with standard positioning (arms above her head). LAO field arrangement was used for both patients. Erythema and fatigue were the only noted side effects.
Proton RT enables delivery of radiation to the chest wall and regional lymphatics, including the IMN, without compromise of coverage and with improved sparing of surrounding normal structures. This treatment is feasible, however, optimal patient set up may vary and field size is limited without multiple fields/matching.
PMCID: PMC3627609  PMID: 23521809
Breast cancer; Treatment planning; Proton beam radiation

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