BACKGROUND:Given numerous publications and clinical trials regarding axillary management in breast cancer, we sought to summarize this complex literature to help clarify this field for clinicians. This systematic review focuses on the role of irradiation of the axillary nodes (locoregional nodal irradiation [LRNI]) in the management of the axilla in patients with early-stage breast cancer in various clinical settings.METHODS:We searched MEDLINE and EMBASE databases, the Cochrane library, the proceedings of the ASCO, the ASTRO, the ESMO, the ESTRO, and the San Antonio Breast Cancer Symposium (2016-2019) meetings. The quality of the studies was assessed with design-specific tools. The study was registered in PROSPERO.RESULTS:We included one systematic review, one individual patient data (IPD) meta-analysis, and five randomized controlled trials (RCTs). After axillary lymph node dissection (ALND), LRNI resulted in small benefits in breast cancer specific mortality, locoregional recurrence, and distant metastases-free survival but not overall survival. After a positive sentinel node biopsy (SLNB), LRNI may provide equivalent locoregional control and disease-free survival (DFS) compared to ALND with a lower risk of lymphedema. No randomized data is available for the neoadjuvant setting.CONCLUSIONS:The summary of the role of radiation, is relevant to radiation oncologists for choosing the correct cohort of patient requiring LRNI and to surgeons making clinical decisions regarding the timing and type of breast reconstruction offered to patients.

Abstract Background Whole breast irradiation (WBI) after lumpectomy reduces the risk of local recurrence, thereby avoiding subsequent mastectomy. It is a key component of breast conserving therapy. WBI is usually given in daily fractions over 3-6 weeks. With accelerated partial breast irradiation (APBI), radiation is delivered over a week or less to the surgical cavity with a margin of normal tissue. It was introduced to provide treatment in a shorter more convenient form. 3D-CRT is an attractive approach as it is non-invasive and uses standard techniques for external beam RT that are widely available. The objective of the RAPID trial was to determine if APBI using 3D-CRT was not inferior to WBI following breast conserving surgery (BCS). Methods Women ≥40 years of age with axillary node-negative invasive ductal carcinoma, or ductal carcinoma in situ (DCIS) ≤3cm treated by BCS with clear margins of excision were eligible. Randomization was stratified for age (< or ≥50y), histology (DCIS alone or invasive breast cancer), tumor size (< or ≥1.5cm), ER status (+/-) if invasive disease, and treatment center. Patients were allocated to APBI using 3D-CRT (38.5Gy in 10 fractions delivered twice daily) or WBI (42.5Gy in 16 daily fractions or 50Gy in 25 daily fractions; boost radiation was permitted). The primary outcome was ipsilateral breast tumor recurrence (IBTR). Important secondary outcomes included radiation toxicity and nurse assessed adverse cosmesis (fair or poor on global assessment). The trial was designed to show that the 5-year IBTR rate in the APBI arm was not inferior to the WBI arm by more than 1.5% (hazard ratio [HR] ≤ 2.02) with 85% power and a one-sided alpha of 5%. Results From February 2006 to July 2011, 2135 patients from sites in Canada, Australia, and New Zealand were randomly assigned: 1070 to APBI and 1065 to WBI. The median follow-up was 8.6 years. The mean age of the study population was 61 years; 82% of patients had invasive breast cancer and 18% had DCIS only. For invasive cancers: 60% were < 1.5cm and 90% were ER positive. For DCIS tumors: 68% were < 1.5cm. A total of 65 IBTRs were observed. For the APBI patients, the 5-year and 8-year cumulative rates of IBTR were 2.3% and 3.0%, respectively. The corresponding data for the WBI patients were 1.7% and 2.8%. The HR for APBI versus WBI was 1.27, 90% confidence interval, 0.84 to 1.91. Acute radiation toxicity (occurring within 3 months of treatment start) e.g. radiation dermatitis and breast swelling was less in patients treated with APBI compared with WBI (≥ Grade 2, 28% vs 45%, p<0.001). Late radiation toxicity (beyond 3 months) e.g. breast induration and telangiectasia was greater in patients treated with APBI (≥ Grade 2, 32% vs 13%, p<0.001 and Grade 3, 4.5% vs 1.0%, p<0.001). Adverse cosmesis was higher in patients treated with APBI compared with WBI at 3 years (29% vs 17%, p<0.001) and at 5 years (32% vs 16%, p<0.001). Conclusions The APBI regimen used in our trial was non-inferior to WBI in preventing local recurrence. Although it was associated with less acute toxicity, an increase in late normal tissue toxicity and adverse cosmesis was observed with APBI. Citation Format: Whelan T, Julian J, Levine M, Berrang T, Kim D-H, Gu CS, Germain I, Nichol A, Akra M, Lavertu S, Germain F, Fyles A, Trotter T, Perera F, Balkwill S, Chafe S, McGowan T, Muanza T, Beckham W, Chua B, Olivotto I. RAPID: A randomized trial of accelerated partial breast irradiation using 3-dimensional conformal radiotherapy (3D-CRT) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-03.

Purpose/Objective(s): A retrospective chart review was conducted to determine if there was any difference in local recurrence rates between two common radiation schedules for adjuvant whole breast radiation in early stage breast carcinoma.Materials/Methods: There were 499 patients with T1-T2, NO breast carcinoma treated with breast conserving surgery and whole breast radiation and without adjuvant systemic treatment at a single institution from January 1985 to December 1992.There were two commonly used fractionation schedules at this time.The first was 5000 cGy in 25 fractions over 5 weeks and the second was 4000 cGy in 15 or 16 fractions plus a boost of 500-1250 cGy in 3-5 fractions.Kaplan-Meir estimates of time to local-recurrence were calculated for the two groups.Results: The median follow-up was 17.4 years.The median age was 60.There were 191 (38.3%) patients treated with 5000 cGy in 25 fractions and 308 (61.7%) patients treated with 4000 cGy in 15/16 fractions plus a boost.The most commonly used boost fractionation was 1250 cGy in 5 fractions in 170 patients (55%).There was no statistically significant difference in local recurrence rate between the two fractionation schedules.The 5, 10 and 15 year local failure rate was 4.9%, 10.7% and 12.5% for the 15/16 fractions plus boost group and 2.7%, 13.1% and 19.2% for the 25 fraction group.Conclusions: Standard whole breast radiation with 5000/25 without a boost results in similar local controls rates as a hypofractionated schedule which includes a boost.Therefore, the practice of boosting all breast patients may not be necessary when using a standard fractionation schedule.

As taxanes have become integrated into routine oncologic use, concerns have arisen over the association between taxanes and radiation toxicities such as pneumonitis. Pneumonitis has been reported to occur both with taxane administration alone or, with concurrent or sequential radiation. The purpose of this study is to evaluate radiation pneumonitis from our institutional phase I/II protocol of neoadjuvant FEC chemotherapy followed by weekly docetaxel concurrent with radiation therapy in the treatment of locally advanced breast cancer (LABC). Since August 2009, 32 LABC patients with stage IIB, IIIA, IIIB, or IIIC invasive breast cancer were enrolled to receive protocol based treatment consisting of 3 cycles of intravenous (IV) fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 (FEC) every 3 weeks. Following this, weekly IV docetaxel 35 mg/m2 was administered concurrently with locoregional external beam radiation therapy to a total dose of 45 Gy in 25 fractions followed by a boost of 5.4-9 Gy in 3-5 fractions to gross residual disease. Adverse events were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. A linear regression model was built used to evaluate potential parameters predictive of clinical pneumonitis (grade ≥2). Of the 32 patients enrolled, 7 were excluded from analysis (n = 6, follow-up <4 weeks; n = 1, converted to palliative radiation therapy due to metastatic disease). Twenty-five patients remained for analysis. The median age was 48 years (range 26 to 64 years). Thirteen patients were treated with intensity modulated radiation therapy while 12 were treated using 3D conformal radiation therapy. In total 13 patients (52%) experienced clinical pneumonitis with 6 of these patients (24%) transiently requiring supportive oxygen (grade 3). On linear regression modeling, the use of IMRT (p = 0.08), grade 3 skin toxicity (p = 0.08), and baseline left ventricular ejection fraction (LVEF, p = 0.05) were potentially predictive of symptomatic pneumonitis. Conversely, various heart and lung dose-volume histogram parameters, trastuzumab use, bolus use, disease laterality, total docetaxel dose, were not predictive of symptomatic pneumonitis (p > 0.10). In multivariable modeling, the use of IMRT (p = 0.05) and baseline LVEF (p = 0.03) remained predictive of symptomatic pneumonitis. The use of concurrent weekly docetaxel-based chemoradiation therapy in LABC is associated with symptomatic pneumonitis and may be related to low baseline LVEF and IMRT use. Conventional parameters of low dose volumes of lung and heart irradiated were not predictive of pneumonitis. The relationship of IMRT and taxanes in the development of pneumonitis is likely complex and warrants further investigation.

To examine the effect of the time interval to definitive breast surgery from the time of clinical presentation on local recurrence and survival in node negative invasive breast carcinoma. A chart review was conducted on 570 female patients with stage T1-T2 N0 breast carcinoma treated with conservative breast surgery and whole breast radiation between 1985 and 1992 at a single institution. No patient received adjuvant systemic treatment. Clinical presentation consisted of a mammogram finding or a palpable lump. The intervals from clinical presentation to definitive breast surgery analyzed were 0-4, >4-12 and >12 weeks. The Kaplan-Meier estimates of the time to local recurrence, distant disease-free survival, and cause-specific survival were determined for the three groups. Cox regression analysis was used to evaluate the effect of clinical presentation and time interval to definitive surgery on survival. The median follow-up was 17.4 years. No statistically significant difference was found in local recurrence as a function of time to definitive surgery (p = 0.43). There was no difference in cause-specific survival with lump presentation as a function of time interval. However, with a mammogram presentation there was a trend to improve cause-specific survival with a time interval of <12 weeks to surgery (interaction p = .09). On multivariable analysis for known prognostic factors and including time interval from presentation to surgery, only the interval between clinical presentation and surgery entered the model for distant disease-free survival. This retrospective review suggests that a time interval of >12 weeks to definitive breast surgery may be associated with decreased survival with mammographic presentation and that time interval to surgery may be the most significant factor for distant disease-free survival. This suggests that metastasis in breast carcinoma occur early, before a lump is detectable.

Abstract Background: Taxanes are known to have radiosensitizing properties, by causing cell arrest in the G2 and M phases of the cell cycle. As taxanes have become integrated into routine oncologic use, concerns have arisen over the association between taxanes and radiation toxicities such as pneumonitis. Pneumonitis has been reported to occur both with taxane administration alone or, more commonly, with concurrent or sequential radiation. The purpose of this study is to evaluate radiation pneumonitis from our institutional phase I/II protocol of neoadjuvant FEC chemotherapy followed by weekly docetaxel concurrent with radiotherapy in the treatment of locally advanced breast cancer (LABC). Materials and Methods: Since August 2009, thirty-two LABC patients with stage IIB, IIIA, IIIB, or IIIC invasive breast cancer were enrolled to receive protocol based treatment consisting of 3 cycles of intravenous (IV) fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 (FEC) every 3 weeks. Following this, weekly IV docetaxel 35 mg/m2 was administered concurrently with locoregional external beam radiotherapy to a total dose of 45 Gy in 25 fractions followed by a boost of 5.4-9 Gy in 3–5 fractions to gross residual disease. Adverse events were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. A linear regression model was built used to evaluate potential parameters predictive of clinical pneumonitis (grade ≥2). Results: Of the 32 patients enrolled on this prospective protocol, 7 were excluded from analysis (n = 6, follow-up < 4 weeks; n = 1, converted to palliative radiotherapy due to metastatic disease). Twenty-five patients remained for analysis. The median age was 48 years (range 26 to 64). Thirteen patients were treated with intensity modulated radiation therapy while 12 were treated using 3D conformal radiotherapy. In total 13 patients (52%) experienced clinical pneumonitis with 6 of these patients (24%) transiently requiring supportive oxygen (grade 3). On linear regression modeling, the use of IMRT (p = 0.08), grade 3 skin toxicity (p = 0.08), and baseline left ventricular ejection fraction (LVEF, p = 0.05) were potentially predictive of symptomatic pneumonitis. Conversely, various heart and lung dose-volume histogram parameters, trastuzumab use, bolus use, disease laterality, total docetaxel dose, were not predictive of symptomatic pneumonitis (p > 0.10). In multivariable modeling, the use of IMRT (p = 0.05) and baseline LVEF (0 = 0.03) remained predictive of symptomatic pneumonitis. Conclusion: The use of concurrent weekly docetaxel-based chemoradiotherapy in LABC is associated with significant symptomatic pneumonitis and may be related to low baseline LVEF and the use of IMRT. However, conventional parameters of low dose volumes of lung and heart irradiated were not predictive of pneumonitis. The relationship of the use of IMRT and taxanes in the development of pnemonitis is likely complex and warrants further investigation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-11.

Purpose: To determine if the number of axillary nodes removed is a predictor of recurrence in node negative breast cancer.Materials and methods: Five hundred thirty-six patients with T1-T2, NO invasive breast cancer, treated with lumpectomy and axillary node dissection (AND), were reviewed from January 1, 1986 to December 31, 1992. Patients received radiation to whole breast only, without regional nodal radiation. There was no adjuvant chemotherapy or Tamoxifen given. Patients were grouped according to the number of axillary nodes dissected as follows: 1-5 nodes (91 patients), 6-10 nodes (225 patients) and >10 nodes (220 patients). Hazard ratios and p-values were determined for time to local recurrence, regional recurrence and for disease specific survival.Results: Median follow-up was 11.2 years. The overall local recurrence and regional recurrence rates for the three groups were: 1-5 nodes, 9.9% and 8.8%, respectively, 6-10 nodes, 10.2% and 2.2%, respectively, and >10 nodes, 11.8% and 2.7%, respectively. The effect of number of axillary nodes removed was statistically significant only for regional recurrence (p = 0.017). There was no adverse effect on disease specific survival (p = 0.363).Conclusion: The number of axillary nodes removed predicts only for regional recurrence in node negative breast cancer patients, with less than 6 nodes removed associated with higher regional recurrence. This may have clinical implications with the current practice of sentinel node biopsy (SNB) replacing axillary node dissection in early stage breast cancer. (C) 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 91 (2009) 38-41

Purpose/Objective(s)Breast irradiation after lumpectomy is an integral component of breast conserving therapy. The optimal fractionation for whole breast irradiation is unknown. 50 Gy in 25 fractions in 5 weeks has been widely used, but recently there has been renewed interest in hypofractionation due to potential radiobiological advantages, patient convenience and lower cost. However, long-term effects are a potential concern. The purpose of this study was to determine if an accelerated hypofractionated 3-week schedule was equally effective to a more conventional 5-week schedule for whole breast irradiation. The results were first published at a median follow-up of 69 months (JNCI 2002;94:1143-50).Materials/MethodsWomen with invasive breast cancer treated by lumpectomy with pathologically clear resection margins and negative axillary nodes were randomly assigned to receive whole breast irradiation of 42.5 Gy in 16 fractions over 22 days (arm A) or 50 Gy in 25 fractions over 35 days (arm B). Boost irradiation was not used. The primary outcome was local invasive recurrence in the treated breast. Secondary outcomes included breast cosmesis and late radiation morbidity.ResultsBetween April 1993 and September 1996 1,234 women were randomly assigned to treatment (622 in arm A and 612 in arm B). Median follow-up is now 144 months. Risk for local recurrence at 10 years was 6.2% for arm A and 6.7% for arm B (absolute difference = −0.5%, 95% CI −3.5%, 2.5%). At 10 years, 70% of arm A patients had a good or excellent cosmetic outcome compared to 71% for arm B (absolute difference = 1.5%, 95% CI −6.9%, 9.8%). The incidence of moderate and severe late radiation morbidity at 10 years to the skin was 6% and 3%, respectively, and to subcutaneous tissue was 8% and 4%, respectively. No differences were detected between treatment arms.ConclusionsAccelerated hypofractionated whole breast irradiation was associated with excellent long-term local control and limited late morbidity, similar to that seen with conventional fractionation for whole breast irradiation. Given the benefits of convenience and cost, such an approach should be considered for women with early breast cancer. Purpose/Objective(s)Breast irradiation after lumpectomy is an integral component of breast conserving therapy. The optimal fractionation for whole breast irradiation is unknown. 50 Gy in 25 fractions in 5 weeks has been widely used, but recently there has been renewed interest in hypofractionation due to potential radiobiological advantages, patient convenience and lower cost. However, long-term effects are a potential concern. The purpose of this study was to determine if an accelerated hypofractionated 3-week schedule was equally effective to a more conventional 5-week schedule for whole breast irradiation. The results were first published at a median follow-up of 69 months (JNCI 2002;94:1143-50). Breast irradiation after lumpectomy is an integral component of breast conserving therapy. The optimal fractionation for whole breast irradiation is unknown. 50 Gy in 25 fractions in 5 weeks has been widely used, but recently there has been renewed interest in hypofractionation due to potential radiobiological advantages, patient convenience and lower cost. However, long-term effects are a potential concern. The purpose of this study was to determine if an accelerated hypofractionated 3-week schedule was equally effective to a more conventional 5-week schedule for whole breast irradiation. The results were first published at a median follow-up of 69 months (JNCI 2002;94:1143-50). Materials/MethodsWomen with invasive breast cancer treated by lumpectomy with pathologically clear resection margins and negative axillary nodes were randomly assigned to receive whole breast irradiation of 42.5 Gy in 16 fractions over 22 days (arm A) or 50 Gy in 25 fractions over 35 days (arm B). Boost irradiation was not used. The primary outcome was local invasive recurrence in the treated breast. Secondary outcomes included breast cosmesis and late radiation morbidity. Women with invasive breast cancer treated by lumpectomy with pathologically clear resection margins and negative axillary nodes were randomly assigned to receive whole breast irradiation of 42.5 Gy in 16 fractions over 22 days (arm A) or 50 Gy in 25 fractions over 35 days (arm B). Boost irradiation was not used. The primary outcome was local invasive recurrence in the treated breast. Secondary outcomes included breast cosmesis and late radiation morbidity. ResultsBetween April 1993 and September 1996 1,234 women were randomly assigned to treatment (622 in arm A and 612 in arm B). Median follow-up is now 144 months. Risk for local recurrence at 10 years was 6.2% for arm A and 6.7% for arm B (absolute difference = −0.5%, 95% CI −3.5%, 2.5%). At 10 years, 70% of arm A patients had a good or excellent cosmetic outcome compared to 71% for arm B (absolute difference = 1.5%, 95% CI −6.9%, 9.8%). The incidence of moderate and severe late radiation morbidity at 10 years to the skin was 6% and 3%, respectively, and to subcutaneous tissue was 8% and 4%, respectively. No differences were detected between treatment arms. Between April 1993 and September 1996 1,234 women were randomly assigned to treatment (622 in arm A and 612 in arm B). Median follow-up is now 144 months. Risk for local recurrence at 10 years was 6.2% for arm A and 6.7% for arm B (absolute difference = −0.5%, 95% CI −3.5%, 2.5%). At 10 years, 70% of arm A patients had a good or excellent cosmetic outcome compared to 71% for arm B (absolute difference = 1.5%, 95% CI −6.9%, 9.8%). The incidence of moderate and severe late radiation morbidity at 10 years to the skin was 6% and 3%, respectively, and to subcutaneous tissue was 8% and 4%, respectively. No differences were detected between treatment arms. ConclusionsAccelerated hypofractionated whole breast irradiation was associated with excellent long-term local control and limited late morbidity, similar to that seen with conventional fractionation for whole breast irradiation. Given the benefits of convenience and cost, such an approach should be considered for women with early breast cancer. Accelerated hypofractionated whole breast irradiation was associated with excellent long-term local control and limited late morbidity, similar to that seen with conventional fractionation for whole breast irradiation. Given the benefits of convenience and cost, such an approach should be considered for women with early breast cancer.

Purpose: To examine the effect of clinical presentation and interval to breast surgery on local recurrence and survival in early-stage breast cancer.Methods and Materials: The data from 397 patients with Stage T1-T2N0 breast carcinoma treated with conservative surgery and breast radiotherapy between 1985 and 1992 were reviewed at the London Regional Cancer Program. The clinical presentation consisted of a mammogram finding or a palpable lump. The intervals from clinical presentation to definitive breast surgery used for analysis were 0-4, >4-12, and >12 weeks. The Kaplan-Meier estimates of the time to local recurrence, disease-free survival, and cause-specific survival were determined for the three groups. Cox regression analysis was used to evaluate the effect of clinical presentation and interval to definitive surgery on survival.Results: The median follow-up was 11.2 years. No statistically significant difference was found in local recurrence as a function of the interval to definitive surgery (p = .424). A significant difference was noted in disease-free survival (p = .040) and cause-specific survival (p = .006) with an interval of >12 weeks to definitive breast surgery. However, the interval to definitive surgery was dependent on the presentation for cause-specific survival, with a substantial effect for patients with a mammographic presentation and a negligible effect for patients with a lump presentation (interaction p = .041).Conclusion: The results of this study suggest that an interval of >12 weeks to breast surgery might be associated with decreased survival for patients with a mammographic presentation, but it appeared to have no effect on survival for patients presenting with a palpable breast lump. (C) 2009 Elsevier Inc.

Purpose: This retrospective review was conducted to determine if delay in the start of radiotherapy after conservative breast surgery had any detrimental effect on local recurrence or disease-free survival in node-negative breast cancer patients. Methods and Materials: A total of 568 patients with T1 and T2, N0 breast cancer were treated with breast-conserving surgery and breast irradiation, without adjuvant systemic therapy, between January 1, 1985 and December 31, 1992 at the London Regional Cancer Centre. The time intervals from definitive breast surgery to breast irradiation used for analysis were 0 to 8 weeks (201 patients), greater than 8 to 12 weeks (235 patients), greater than 12 to 16 weeks (91 patients), and greater than 16 weeks (41 patients). Kaplan-Meier estimates of time to local-recurrence and disease-free survival rates were calculated. Results: Median follow-up was 11.2 years. Patients in all 4 time intervals were similar in terms of age and pathologic features. No statistically significant difference was seen between the 4 groups in local recurrence or disease-free survival with surgery radiotherapy interval (p = 0.521 and p = 0.222, respectively). The overall local-recurrence rate at 5 and 10 years was 4.6% and 11.3%, respectively. The overall disease-free survival at 5 and 10 years was 79.6% and 67.0%, respectively. Conclusion: This retrospective study suggests that delay in the start of breast irradiation of up to 16 weeks from definitive surgery does not increase the risk of recurrence in node-negative breast cancer patients. The certainty of these results is limited by the retrospective nature of this analysis.