Postmastectomy Radiation Research Articles

Proton vs. Photons for Breast Cancer Patients with Immediate, Implant-Based Reconstruction Receiving Postmastectomy Radiotherapy: A Multicenter Pooled Analysis

Proton therapy improves postmastectomy radiotherapy (PMRT) normal tissue sparing compared with photon techniques. However, little is understood about its effect on reconstruction outcomes. The primary objective was to evaluate complication rates in breast cancer patients treated with proton (PRO) versus photon (PHO) PMRT following immediate, implant-based breast reconstruction. Consecutive patients with breast cancer who underwent mastectomy and immediate reconstruction with a tissue expander (TE) or permanent implant (PI) and PRO or PHO PMRT between 2011 and 2022 were included from two institutions. Complication rate was defined as the sum of reconstruction failure (explantation without replacement), unplanned prosthesis exchange, and other unplanned revisional surgery. Each complication type was analyzed as an independent endpoint. Among 733 patients, median follow-up was 4.4 years; 36.5% (267) were treated with PRO and 63.5% (466) with PHO. There was no difference in age, BMI, or comorbidities between the two groups. PRO was more likely to have had, two-stage reconstruction and pre-pectoral implant placement (p<.01). Median dose was 50-50.4 Gy in 25-28 fractions, with only 50 receiving hypofractionation. Bolus was used in all PHO patients. Regional nodes were more likely to be included in PRO (99.6% v. 83.7% PHO, p<.01). Although there was no difference in the use of chest wall boost between groups, the axillary nodes were more frequently boosted in PRO (25.1% vs 2.8% PHO, p<.01). The overall rate of complications at 4 years was 26.7% (95% CI = 23.3-30.5). The 4-year rate of reconstruction failure, unplanned exchange, and other surgery was 8.2% (95% CI = 6.3-10.7), 17.4% (95% CI = 14.6-20.8), and 12.5% (95% CI = 10.1-15.5), respectively. On MVA, PRO did not confer an increased risk of reconstruction complications compared to PHO. Significant risk factors for reconstruction failure included TE-to-autologous approach [HR versus direct-to-implant reference: 4.05 (95% CI = 1.60-10.22)], TE-to-permanent implant approach [HR = 2.06 (95% CI = 1.12-3.79)], chest wall boost [HR = 2.20 (95% CI = 1.21-4.02)], and any lymph node boost [HR = 2.33 (95% CI = 1.10-4.97)]. Compared to direct-to-implant, two-stage reconstruction was also associated with a higher rate of unplanned exchange [HR for TE/PI = 1.49 (95% CI = 1.01-2.20)] and revisional surgery [HR for TE-to-autologous = 3.95 (95% CI = 1.64-9.52)]. Prepectoral implant placement was correlated with reduced risk of revisional surgery, relative to subpectoral placement [HR = 0.42 (95% CI = 0.22-0.81)]. This represents the largest combined series to date comparing PRO and PHO PMRT. Despite a higher rate of two-stage reconstruction, nodal irradiation, and nodal boost in PRO, there was no significant difference in the risk of complications between protons and photons. Differences in PRO delivery techniques between institutions and dosimetric details such as skin dose will be presented in person.

Interim Analysis of a Non-Randomized Prospective Trial Comparing Hypofractionated Post-Mastectomy Radiotherapy (HF-PMRT) to Conventional Post-Mastectomy Radiotherapy (CF-PMRT) for Breast Cancer (BC) Patients

The standard of care for treatment for LABC patients who have undergone modified radical mastectomy (MRM) is PMRT. Post-mastectomy RT (PMRT) for LABC patients has been established in three trials to improve locoregional control and overall survival (OS). A published trial from China showed that HF-PMRT was non-inferior to CF-PMRT. This study was conducted to determine if HF-PMRT can provide similar efficacy and toxicity. A non-randomized prospective trial design was employed to compare HF-PMRT and CF-PMRT in post-MRM BC patients. Patients with pathologically proven BC who underwent MRM without positive margins and with less than 8 positive nodes were included. Informed consent was obtained. Patients decided which treatment they will receive. They received either HF-PMRT of 43.2 Gy in 16 fractions (fx) [2.7 Gy/fx] or CF-PMRT of 50-50.4 Gy in 1.8-2.0 Gy/fx to both chest wall and regional nodes (axillary and supraclavicular) in both regimens. Primary endpoints were 2-year OS and 2-year local recurrence free survival (LRFS). Secondary endpoints include acute and late toxicities. Analysis was done as intention-to treat. An interim analysis of 2-year results is presented. A total of 37 patients were enrolled in two separate cohorts: a single-arm cohort that recruited 10 HF-PMRT patients from 2014-2015 and a two-arm prospective trial that started recruitment last 2019 and included 12 HF-PMRT and 15 CF-PMRT patients. Median follow-up was 35 months. There were more Stage IIB and Stage III for the CF-PMRT arm [p = 0.040]. Treatment interruptions were more frequent in the CF-PMRT arm (100% vs 68%, p = 0.028). The duration of interruption was also longer in CF-PMRT (median 8 vs 3 days) [p < 0.003]. Acute and late toxicities were not statistically different. There was one patient each with RTOG Grade 2 acute skin toxicity in the HF-PMRT (4.55%) and CF-PMRT arms (6.67%) [p = 0.703]. For late toxicities, the HF-PMRT arm had 6 Grade 1 late skin toxicities and 1 Grade 3 late skin toxicity vs 1 Grade 1 late skin toxicity for CF-PMRT arm [p = 0.196]. 2-year OS rate (86.3% vs 100%, p = 0.403) 2-year DFS rate (68.18% and 73.33%, p = 0.126) were both not statistically different. There were no reported locoregional recurrences (LCR). In terms of local control, both arms have showed no LCRs. 2-year OS and DFS rate were no different. As the study has not yet reached the adequate sample size, the non-inferiority of HF-PMRT cannot be definitively concluded. Acute and late toxicities were no different. There was a significantly higher rate of treatment interruptions in the CF-PMRT compared to the HF-PMRT arm. The results of this interim analysis prove to be promising and patients will continue to be accrued. The final results of this study might have tremendous implications in local practice.

Disparities in Breast-Conserving Therapy vs. Mastectomy among Asian American and Pacific Islander Women

Multiple randomized trials support the use of breast-conserving therapy (BCT), defined as lumpectomy followed by adjuvant radiotherapy, as an alternative to mastectomy for definitive treatment of early-stage (T1-2N0) breast cancer. However, data suggest that Asian American, Native Hawaiian, and Pacific Islander (AANHPI) may undergo mastectomy at higher rates than BCT and may experience barriers to receipt of BCT. The purpose of this study was to examine BCT utilization by disaggregated AANHPI groups to identify differences in receipt of mastectomy versus BCT. The 2004-2017 National Cancer Database was queried to identify women age ≥18 years old diagnosed with cT1-2N0M0 breast cancer treated with either BCT or mastectomy without post-mastectomy radiation therapy. Women were classified based on self-reported race. Multivariable logistic regression defined adjusted odds ratios (OR) assessing the association between race and receipt of BCT versus mastectomy for all patients and separately by cT1-2 stage. All models were adjusted for relevant sociodemographic and clinical factors. Of 794,403 women with cT1-2N0M0 breast cancer, 239,801 (30%) received mastectomy and 554,602 (70%) received BCT. After adjusting for clinical and sociodemographic factors, AANHPI women had greater odds of receiving mastectomy over BCT, compared to White women (OR [95% CI], 1.35 [1.30-1.39]; p<0.001). In contrast, Black women were less likely than White women to receive mastectomy (0.86 [0.84-0.87]; p<0.001). Upon disaggregation, Chinese, Japanese, Filipino, Korean, Vietnamese, and Asian Indian & Pakistani women were more likely to receive mastectomy over BCT compared to White women (p<0.001 for all). Treatment at academic (1.30 [1.27-1.32]), integrated (1.24 [1.21-1.27]), and comprehensive community cancer centers (1.15 [1.13-1.17]) were all associated with greater odds of mastectomy compared to treatment at community cancer programs (all p<0.001). Greater distance from treatment facility (≥50 mi. vs. 0 to <10 mi. [reference], OR 1.50 [1.47-1.53]) and cT2 disease (1.85 [1.82-1.87]) were also associated with greater odds of receiving mastectomy (all p<0.001). In this evaluation of women with early-stage breast cancer, women from several AANHPI groups were more likely to receive mastectomy (as opposed to BCT) compared to White women. While sociocultural preferences, differences in access to and interest in reconstruction, as well as prevalent tumor-to-breast ratios may partially explain the disparities, collectively our data suggest an ongoing need for greater patient involvement in shared-decision making, particularly in vulnerable and understudied Asian populations.

Phase I-II Study of Prone Hypofractionated Accelerated Breast and Nodal Intensity Modulated Radiation Therapy

In patients (pts) with breast cancer, prone radiation therapy (RT) has been shown to reduce heart and lung dose which may decrease late toxicity. Routinely used for whole breast irradiation, its use to treat regional lymph nodes (LNs) is not widespread. In this phase I-II study, pts treated with partial mastectomy or mastectomy with 1-5 pathologically involved LNs underwent whole breast or post-mastectomy RT plus regional nodal irradiation using IMRT to the supraclavicular and level III axillary LNs. Pts who underwent sentinel LN biopsy (SLNB) alone (no axillary dissection) had the level I and II axillary LNs included in the RT field. 40.5Gy in 15 daily 2.7Gy fractions with daily concomitant 0.5Gy tumor bed boost was prescribed. Normal tissue dose constraints included heart V5Gy<5%, ipsilateral lung V10Gy<20%, contralateral lung V5Gy<15%, ipsilateral brachial plexus (BP) maximal dose (Dmax)<43Gy, spinal cord Dmax≤37.5Gy, spinal cord + 0.5cm Dmax<41Gy, thyroid contralateral lobe Dmax<16Gy, esophagus V30Gy<50% and Dmax≤40.5Gy. The primary endpoints were dosimetric feasibility and incidence of >grade 2 acute toxicity according to CTCAE, v3.0. The secondary endpoint was late toxicity. Exploratory outcomes were local recurrence, disease free survival (DFS), and overall survival (OS). Between January 2011 to December 2016, 97 pts with stage IB-IIA breast cancer were enrolled. 66 pts underwent partial mastectomy and 31 pts underwent mastectomy. 16 pts had SLNB alone. 33% (95% CI: 23.8%, 43.3%) met all protocol dose constraints. Heart, contralateral lung, spinal cord and esophagus V30Gy constraints were met by all pts. The ipsilateral lung constraint was met in 95% (95% CI: 88.6%, 98.4%) of plans with a mean V10Gy of 9.44% (SD: 6.08). The BP Dmax constraint was exceeded in 31.6% (95% CI: 22.4%, 41.9%) of plans with a mean increase of 2.86 Gy (SD: 7.92 Gy) over target. The esophageal Dmax<40.5Gy constraint was exceeded in 6 plans with an increase in 0.74 Gy (SD: 0.46 Gy) over target. There were no grade 3 acute toxicities meeting the primary toxicity endpoint. Common acute low-grade toxicities by pt included fatigue (grade 1: 54 [56%]; grade 2: 2 [2%]), esophagitis (grade 1: 8 [8%]; grade 2: 2 [2%]), dermatitis (grade 1: 81 [84%]; grade 2: 6 [6%]). At median and maximum follow up of 8.02 (IQR: 3.31) and 13.3 years, respectively, there were 2 local recurrences (2.1%). DFS and OS were 86.6% (95% CI: 78.2%, 92.7%) and 90.7% (95% CI: 83.1%, 95.7%), respectively. The incidence of pts with maximum grade 1, 2 and 3 late toxicities were 39 (40%), 14 (14%), and 2 (2%), respectively. The maximum grade late toxicities included 1 grade 3 retraction and 2 grade 3 asymmetries. There was no brachial plexopathy or pneumonitis. Patients treated with prone hypofractionated hybrid breast/chest wall tangents and IMRT to the regional LNs demonstrate excellent dosimetry to the heart, lungs and spinal cord, minimal acute and late toxicity and excellent clinical outcomes. PMID: 26723552.

A Phase II, Randomized, Double Blind, Placebo Controlled Study of the Safety and Efficacy of a Caffeine-Based Antifibrosis Cream in Patients with Breast Cancer Undergoing Radiation Therapy

Radiation induced fibrosis (RIF) is a common long term adverse event in patients undergoing post-mastectomy radiation therapy (PMRT) which can cause capsular contracture, implant loss, and reconstruction complications in women with implant-based breast reconstruction. At a molecular level, adenosine is a driver of RIF. Preclinical data have shown that pharmacologic blockade of the adenosine A2A Receptor (A2AR) in mice as well as an A2AR knockout mouse model prevented skin fibrosis associated with radiation injury. Caffeine is an A2AR antagonist which has been shown to block the development of hepatic fibrosis in liver disease patients. We present a phase II placebo controlled clinical trial to evaluate whether a caffeine-based cream can prevent RIF and thus reduce the rates of reconstructive complications in patients with tissue expander-based reconstruction requiring PMRT. Women ≥ 18 years old with breast carcinoma stage 0-III status post mastectomy with tissue expander-based reconstruction who require PMRT to the chest wall +/- the regional nodes are being enrolled. The target accrual is 60 patients. Boost field to the chest wall, scar and/or nodal region is allowed. Patients with inflammatory breast cancer or those requiring skin bolus are excluded. Prior to starting radiation, patients will be randomized to placebo vs. caffeine cream and they will be instructed to apply the cream twice a day starting on the first day of radiation treatment and continuing daily for the duration of radiation until the removal of tissue expanders. The primary study endpoint is reconstructive complications requiring rehospitalization or reoperation by 2 years post radiation including reconstructive failure with or without reconstruction. A safety endpoint of grade ≥ 2 acute radiation dermatitis will also serve as a co-primary endpoint. Secondary endpoints are wound infection/cellulitis, hematoma, seroma, threatened exposure, wound dehiscence, implant leakage, rupture, and or deflation, and capsular contracture that do not meet criteria for the primary endpoint. Clinician rated cosmesis, local recurrence, regional recurrence, distant metastasis and survival up to 4 years are additional secondary endpoints. Exploratory endpoint includes the use of shear wave elastography (SWE) as a potential tool to quantitatively measure post irradiation fibrosis. Correlative aims include assessing epidermal thickness and fat layer thickness from tissue obtained at time of implant exchange for association with the development of fibrosis. The primary efficacy endpoint will be estimated using Kaplan Meier methods from date of randomization. Treatment comparisons will be based on a 2-sided log rank chi-square test and the hazard ratio will be estimated with 95% confidence intervals. The study started accruing in 12/2019 and is estimated to end by 04/2024. As of January 2023, 67% (40/60 patients) of the planned patients have been enrolled. To be determined. To be determined.

Newly Diagnosed Mental Health Disorders in Patients with Breast Cancer Receiving Radiation Therapy

Patients with a mental health disorder (MHD) have higher age-adjusted mortality compared to the general population. There are few reports investigating the factors that contribute to newly diagnosed MHD following the diagnosis and treatment of breast cancer. Here, we report the incidence of acquired MHD after the diagnosis and treatment of breast cancer in patients who received radiation therapy. A database query of a single institution, prospectively maintained database identified patients diagnosed with breast cancer who received whole or partial breast irradiation (WB/PBI) or post-mastectomy radiotherapy (PMRT). A second query of the patients' electronic medical record cross-referenced those patients with ICD-10 mental health diagnosis codes (F1-F99) that were newly acquired following the diagnosis of breast cancer. Univariable and multivariable analyses were performed, analyzing the effect of multiple factors on new mental health diagnoses. Odds ratios (OR) were calculated with a linear regression model, examining demographic characteristics, cancer stage, surgery type, receipt of chemotherapy or hormone therapy, insurance type, and substance use. We identified 1129 patients, aged 26 - 92 years at the time of breast cancer diagnosis, who were treated at our institution between 2012 and 2017. 136 patients had a pre-existing MHD and were excluded from the analysis. 714 (74%) received WB/PBI, and 254 (26%) received PMRT with a median follow up of 63 months. 318 patients (33%) were diagnosed with MHD following breast cancer diagnosis. Median time to diagnosis of MHD was 30 months following the initial breast biopsy. On univariable (UVA) and multivariable analysis (MVA), N+ disease (UVA OR = 1.70, p<0.001), mastectomy (UVA OR = 1.55, p<0.01), receipt of chemotherapy (MVA OR = 1.77, p<0.0001), divorced relationship status (MVA OR = 2.38, p = 0.007), and retired employment status (MVA OR = 1.93, p<0.0001) conferred an increased risk of developing MHD. The primary new MHD identified following completion of radiation therapy included anxiety related disorders (44.4%), depression related disorders (19.4%), tobacco use disorder (12.9%), and dementia related disorders (6.2%). One in three patients treated with radiation therapy developed a new MHD following the diagnosis of breast cancer in this cohort. The majority of acquired MHD in this study were depression and anxiety related disorders. Patients who received chemotherapy, were divorced, or were retired were at a higher risk of developing MHD following breast cancer diagnosis. Further prospective studies are needed to identify potential interventions that would benefit this at-risk population.

Quality Assurance in a Phase III, Multicenter, Randomized Trial of POstmastectomy radioThErapy in Node posiTive Breast Cancer with or without Internal mAmmary nodaL Irradiation (POTENTIAL): A Planning Dummy Run

To report the planning dummy run results of the POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL) trial-a multicenter, randomized, phase 3 trial-to evaluate postmastectomy radiotherapy, with or without internal mammary nodal irradiation, for patients with high-risk breast cancer. All participating institutions were provided the contours of the dummy run case, and they generated radiotherapy (RT) plans per protocol guidelines. The plans were reviewed and feedback were provided by the quality assurance team, after which the institutions resubmitted revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed both in the primary and final submission. Theplans from 26 institutions were included in the analysis. A number of major deviations were found in the primary submission, such as less strict constraint on organs at risk (OARs) V5Gy, and no application of chest wall skin flash. The protocol compliance rates of the dose coverage for the planning target volume of the chest wall (PTVcw), PTV of supra/infraclavicular fossa plus axilla levels I, II, III (PTVsc+ax), and PTV of the IMN region (PTVim) were all significantly improved in the final submission compared with those in the primary submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8, respectively. For OARs, the protocol compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. All major deviations were corrected and protocol compliance was significantly improved and of high level in the final submission. Moreover, the variations were reduced. Therefore, a planning dummy run was essential to guarantee good RT plan quality and inter-institutional consistency for multicenter trials.

Impact of the New ESTRO-ACROP Target Volume Delineation Guideline on Breast-Related Complications after Implant-Based Reconstruction and Postmastectomy Radiotherapy

The European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice (ESTRO-ACROP) recently updated a new target volume delineation guideline for postmastectomy radiotherapy (PMRT) after implant-based reconstruction. This study aimed whether this change has impact on breast-related complications. We retrospectively reviewed patients who underwent PMRT after mastectomy with tissue expander or permanent implant insertion from 2016 to 2021. In total, 412 patients were included; 277 received RT by the new ESTRO-ACROP target delineation (ESTRO-T), and 135 received RT by conventional target delineation (CONV-T). The primary endpoint was comparison between the target groups of major breast-related complication, including infection, capsular contracture, deformity and necrosis requiring re-operation or re-hospitalization during follow-up after RT or delayed implant replacement. Complications were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0., and capsular contracture was graded by the Baker Classification. The median follow-up was 29.5 months (range, 0.3-76.8). The 1-, 2-, and 3-year incidence rates of major breast-related complication were 5.7%, 10.0%, and 11.6% in the ESTRO-T group, and 8.2%, 13.8%, and 14.7% in the CONV-T groups; it did not show a difference between the groups (P = 0.55). In multivariate analyses, target delineation is not significantly associated with the major complications (hazard ratio [HR] = 0.93; P = 0.83, Table 1). There was no significant difference between the ESTRO-T and CONV-T groups in the incidence of any breast-related complications (3-year cumulative incidence, 37.3% vs. 29.4%, respectively; P = 0.28). Symptomatic RT-induced pneumonitis rates were 2.7% in the ESTRO-T group (7 patients) and 2.2% in the CONV-T group (3 patients). Only one local recurrence event occurred in the ESTRO-T group, which was within the ESTRO-target volume. Target volume delineation according to the new ESTRO-ACROP guideline did not reduce the risk of major or any breast-related complications. As the dosimetric benefits of heart and lung have been reported, further analyses with long-term follow-up are necessary to evaluate whether it could be connected to better clinical outcomes.

Patterns and Longitudinal Changes in The Practice of Breast Cancer Radiotherapy in Korea: Korean Radiation Oncology Group 22-01

To analyze contemporary practice patterns in breast cancer radiotherapy (RT) and to assess longitudinal changes therein over 5 years in Korea. A nationwide survey was conducted among board-certified radiation oncologists in Korea by the Division for Breast Cancer of the Korean Radiation Oncology Group in March 2022. The survey consisted of 44 questions related to six domains: hypofractionated (HypoFx) whole breast RT, accelerated partial breast RT (APBI), regional nodal irradiation (RNI), RT for ductal carcinoma in situ (DCIS), postmastectomy RT (PMRT), and tumor bed boost. In total, 70 radiation oncologists from 61 of 101 (60%) institutions participated in the survey. HypoFx RT was used by 62 respondents (89%), which has significantly increased from 36% in 2017. The HypoFx RT was commonly administered at 40-42.5 Gy in 15-16 fractions. APBI was used by 12 respondents (17%), which has increased from 5% in 2017. The use of RNI did not change significantly: ≥ pN2 (6%), ≥ pN1 (33%), and ≥ pN1 with pathological risk factors (61%). However, the indications for use of internal mammary lymph node (IMN) irradiation have expanded. In particular, the rates of routine treatment of IMN (11% from 6% in 2017) and treatment in cases of ≥ pN2 (27% from 14% in 2017) have doubled; however, the rate of treatment for only IMN involvement, identified on imaging, has decreased to 31% from 47% in 2017. With regard to DCIS, the use of hypoFx RT increased to 75% from 25%, and the rate of omission on of RT after breast-conserving surgery decreased to 38% from 48% in 2017. The use of hypoFx RT for PMRT also increased to 36% from 8% in 2017. The adoption of HypoFx RT after breast-conserving surgery in invasive breast cancer and DCIS has increased significantly, whereas that for PMRT has increased moderately, compared to 2017. Further studies are required to determine the optimal use of RNI.

Increased Complication Rates with Proton Therapy in Breast Cancer Patients with Immediate, Implant-Based Reconstruction: Single-Institution Comparative Effectiveness Analysis

To compare the impact of protons vs. photons on breast reconstruction complications, for patients (pts) receiving postmastectomy radiation (PMRT) with either single-stage direct-to-implant (DTI) or two-staged expander/implant (TE/I). We reviewed the charts of 578 pts who underwent immediate reconstruction followed by radiation at our institution between 2010 and 2020. Pts with implant-based reconstruction using either TE/I or DTI and PMRT delivery in the presence of the prosthesis were included. Pts enrolled in active ongoing clinical trials were excluded from the analysis. The photon group received 3D conformal or IMRT/VMAT treatment with a median dose of 50-50.4 Gy in 25 to 28 fractions. For proton pts, treatment was delivered mainly with pencil beam scanning technique (PBS); few pts received passively scattered proton spread-out Bragg peak (SOBP). The complications were defined as infection/skin necrosis (I/N) requiring operative debridement, capsular contracture (CC) necessitating capsulotomy, and overall implant failure (ORF) as the removal of the permanent implant irrespective of replacement outcomes (i.e., with and without salvage reconstruction). We fit inverse-probability weighted cumulative incidence curves to adjust for confounding and non-random loss to follow-up. Various sensitivity analyses were conducted. Four hundred ninety-five pts were available for the final analysis with an overall median follow-up of 55 months. 66 (13%) received protons, of which14 were treated with SOBP protons. 137 (28%) and 256 (56%) received photons with and without chest wall boost (CWB), respectively. The 5-year inverse probability-weighted risk of CC post-PMRT was 31% for protons vs. 10% for photons (RR:3.09, 95% CI: 1.77, 5.40). The 5 years ORF risk was 35.6% in protons compared to 22.7% in photons pts (RR: 1.57; 95% CI 1.0, 2.48). Hazard ratios from the adjusted Cox models were 3.79 (p<0.001) for CC and 2.05 (p<0.01) for ORF. No difference in I/N was noted between protons and photons pts. Sensitivity analysis showed that protons significantly increased CC risk vs photons both with CWB (HR:3.56, P<0.001) and without CWB (HR:3.9, p<0.001). Similar outcomes were observed with ORF, where protons increased the rate of ORF compared to photons, irrespective of CWB (HR 1.8, p = 0.038 with CWB; HR 2.4, p = 0.004 without CWB). No differences between PBS and SOBP proton techniques were noted. Compared to photons, proton therapy increases the risk of capsular contracture requiring surgical intervention and hence overall reconstruction failure. This data should inform discussions about the risks and benefits of protons in patients with reconstruction, while awaiting mature data from ongoing clinical trials (RADCOMP) utilizing protons for breast cancer.

Impact of Post-Mastectomy Radiotherapy on Cosmesis and Quality of Life after Deep Inferior Epigastric Perforator Flap Breast Reconstruction: A Single Institution Experience

Immediate breast reconstruction (IBR) yields better cosmetic results and reduce psychological distress than delayed (DBR). Literature data showed better local cosmesis after reconstruction autologous flaps than prothesis. Our aim is to compare cosmetic results and quality of life (QoL) after PMRT delivered either after IBR or DBR with DIEP flap. We reviewed files of 99 patients (100 DIEPs) treated in our department from January 2000 to December 2019. Patients were divided into 2 groups depending on the treatment sequence: IBR (n = 22) versus DBR (n = 78) followed by PMRT. All the patients had their DIEP flap by the same surgical team. All patients had cosmetic evaluation using Harvard/RTOG cosmesis grading scale. Fifty percent (32 in IBR and 14 in DBR group) of the patients responded to the QoL evaluation using auto questionnaires and BREAST-Q to evaluate breast specific HRQoL and satisfaction. The analysis of cosmetic scores was carried out with a Chi2 test and the analysis of QoL scores with a student test. Kaplan Meier (log-rank test) is used for recurrence-free and overall survival. Median follow-up was 56 months. Median age of the patients was 48 (28-71). In terms of disease stage: T1-2 (52%), N0 (38%). 86% of the patients had chemotherapy either in neo-adjuvant (26%) or adjuvant (60%) settings. Radiation therapy (RT) delivered a total dose ranged between 45 Gy and 50 Gy using 1.8-2.5 Gy/per fraction. Supra-clavicular and internal mammary chain irradiation was performed in 67% and 33% of the patients respectively. After surgery, 15% had post-operative complications such as DIEP necrosis (n = 8) that delayed RT delivery. Among the 99 patients, 3 died from metastatic evolution and were not included in the cosmetic and QoL analyses. Local recurrence rate was slightly higher after DBR (12.5%) as compared to IBR (3.8%). Loco-regional and metastatic recurrence rates were 4.5% and 4.5% after IBR versus 1.3% and 9% after DBR (p = NS). Disease free and overall survival were 88% and 98% at 5y and 66% and 96% at 10y.Good-to-excellent results were observed in 57% in the IBR vs 67% in the DBR (p = 0.92). There was no impact of previous chemotherapy (p = 0.21), tobacco use at diagnosis (p = 0.27), diabetes (p = 0.86), RT timing (p = 0.53) and endocrine therapy administration (p = 0.67). QoL was evaluated with the BREAST-Q self-evaluation for 5 post operative items: psycho-social, physical, sexual well-being and satisfaction with breast and global cosmetic results. Out of the 99 patients, 46% had responded to the QoL evaluation. We found no statistical difference between the two groups for all the BREAST-Q evaluation items. Our center is considered expert for DIEP reconstructions since its development in end of the nineties. Our data showed no impact PMRT using conventional fractionation (with mainly 1.8 Gy/fraction) on cosmetic results, QoL, and patients' satisfaction regardless of the timing of the breast reconstruction. Additional studies are in progress with updates.

Late Toxicity and Patient Satisfaction in Hypofractionated Post-Mastectomy Radiotherapy after Immediate-Autologous Reconstruction

Immediate autologous reconstruction (IAR) is increasingly being used in the context of breast cancer patients (BCP) treated with mastectomy with the need for subsequent radiotherapy treatment. Currently in clinical practice, despite the fact that conventional fractionated RT (CFRT) has been the standard schedule, hypofractionation schemes are becoming increasingly common. Although no results have been reported on tolerance, late toxicity and satisfaction with treatment in this setting. Our aim was to evaluate late side-effects and patient´s satisfaction receiving PMRT after IAR, comparing CFRT vs HFRT. Between June 2015 and February 2020, 47 patients received either CF or HF PMRT after IAR in a tertiary hospital. IAR was performed with latissimus dorsi (LD) or deep inferior epigastric perforator (DIEP) flaps at the time of mastectomy. The prescribed dose was 50 Gy over 25 fractions in the CF schedule and 40.05 Gy over 15 fractions in the HF schedule. The target volume to be treated was the reconstructed chest-wall and the axillary-supraclavicular nodes if indicated, using intensity-modulated radiotherapy treatment technique. Late toxicity was evaluated using CTCAE v.5.0 criteria, and patient´s global satisfaction was assessed using a self-evaluation questionnaire, in which patients answered a series of selected questions related to radiation therapy from the BREAST-Q questionnaire, from 1-5 points. Median age was 48 years (28-77) and median follow-up was 51 months (27-99). 25 patients received HFRT and 22 CFRT. Late side effects after PMRT and tolerance until 3 years with both schedules are shown in Table 1. No relationship was found between incidence of late side effects and RT fractionation. Mean patient´s satisfaction was 3.8 in the CFRT schedule and 4 in the HFRT schedule. According to our findings, HFRT after IAR in post-mastectomy setting seems to be safe and well tolerated, with no high rates of severe late toxicity and with a good level of satisfaction of the treated patients. Table 1. Three years side effects of CRFT and HFRT radiotherapy after mastectomy and immediate autologous reconstruction in 47 patients.

Plan Comparison of Left Breast Postmastectomy Radiotherapy: Halcyon IMRT and VMAT Plan vs. Truebeam Fixed-Jaws Plan

The purpose of this work is to provide a Varian Halcyon planning solution for left breast postmastectomy radiotherapy by comparing the plan quality of Varian Truebeam plan with Halcyon plan. Ten patients who previously received left breast postmastectomy intensity-modulated radiotherapy (IMRT) on Truebeam were retrospectively selected and replanned using Halcyon. The planning target volume (PTV) included chest wall and supraclavicular region, and the prescribed dose was 50 Gy in 25 fractions (2 Gy/F). In addition to the original Truebeam fixed-jaws IMRT (IMRT_T), a Halcyon IMRT (IMRT_H) plan and a Halcyon volumetric-modulated arc therapy (VMAT_H) plan were designed for each patient. The conformity index (CI) and homogeneity index (HI) of the PTVs, and the dose of organs at risk were calculated and compared. Statistical significance was performed using the LSD-t test or Wilcoxon signed-rank test with a significance level of 0.05. The V20 and V30 of ipsilateral lung, the V20, V30 and Dmean of heart, and CI of target area in IMRT_H plan were significantly lower than those in IMRT_T plan (P<0.05). No significant difference was found in the V5, V10 and Dmean of ipsilateral lung, the V5 and Dmean of contralateral lung, the V5 and Dmean of contralateral breast, HI of PTV (P>0.05), but the Dmean of left humeral head in IMRT_H plan was significantly higher than that of IMRT_T plan (P<0.05). All the metrics mentioned above showed higher level in VMAT_H plan than the IMRT_T plan and IMRT_H plan (P<0.05), except for HI (P>0.05) and Dmean of left humeral head (P>0.05 when compared to IMRT_H plan). The IMRT_H plan acts better in OAR sparing and PTV conformity than the IMRT_T plan, while the VMAT-H plan can only parallel the other two techniques in HI. The IMRT_H plan is promising in treating left breast postmastectomy patients with dosimetric improvements.

Lymphocyte Count Kinetics and the Effect of Different Radiotherapy Techniques on Radiation-Induced Lymphopenia in Patients with Breast Cancer Receiving Hypofractionated Postmastectomy Radiotherapy

Radiation-induced lymphopenia (RIL) is associated with poor prognosis in solid tumors. This study aimed to describe the lymphocyte kinetics in patients with breast cancer receiving hypofractionated postmastectomy radiotherapy (RT) and to investigate the association of different RT techniques with RIL. We assessed 607 patients who received hypofractionated postmastectomy RT for breast cancer in our prospective clinical database from 8 hospitals. All patients received irradiation to the chest wall and supraclavicular fossa. RT techniques included integrated RT with the photon-based intensity modulated techniques to irradiate all target volumes (integrated RT) and a hybrid approach combining photon irradiation to supraclavicular nodes and electron irradiation to the chest wall (hybrid RT). Peripheral lymphocyte counts (PLC) were tested prior to RT (baseline), weekly during RT, at 1, 2 weeks, 3, 6 months after RT, and then every 6 months. Grade 3+ RIL was defined as PLC nadir during RT of <0.5 ×103/ml. Mean PLC was compared by the t test. Univariate, multivariate, and propensity score matching (PSM) analyses were used to evaluate the effect of different RT techniques on grade 3+ RIL. During RT, 121 (19.9%) of patients had grade 3+ RIL. The PLC started to recover at 1 week and reached baseline levels 1 year after RT. A greater proportion of the patients treated with the integrated RT (90/269, 33.5%) developed grade 3+ PLC compared with those receiving hybrid RT (31/338, 9.2%, P < 0.001). After conducting PSM, multivariate analyses showed lower baseline PLC (HR = 0.15, P<0.001) and RT technique (the integrated RT vs. hybrid RT, HR = 4.76, P<0.001) were independent risk factors for grade 3+ RIL. The PLC in patients receiving the integrated RT after RT were higher than that in those receiving hybrid RT (p<0.05). RT technique affect the risk of and recovery from RIL, which may impact survival. Choosing appropriate RT technique to minimize RIL might be considered to benefit their outcomes.

Near-Surface Dose Avoidance in Patients with Implant-Based Reconstruction Receiving Post-Mastectomy Proton Irradiation

Dose to the near-surface region may contribute to toxic effects and breast reconstruction complications in patients receiving post-mastectomy irradiation. Here we report the acute and chronic toxic effects in patients with implant-based reconstruction receiving post-mastectomy proton irradiation with prospective near-surface dose avoidance. We reviewed the charts of patients with breast cancer who underwent a mastectomy with implant-based reconstruction and a first course of pencil beam scanning proton irradiation at a single institution from 2017-2022. Patients were evaluated weekly on-treatment, 3- and 12-months post-completion, and then annually. Baseline demographics, treatment details, acute and chronic toxicities (CTCAE v.4), unplanned reconstructive surgery, and implant failure were recorded. Inverse probability weighting was used to generate a balanced cohort receiving post-mastectomy photon irradiation. Logistic regression was used for comparison. Sixteen patients with implant reconstruction at the time of treatment completed proton irradiation with a median follow up of 1.6 years. Nine (56%) underwent direct-to-permanent implant reconstruction and seven (44%) underwent two-stage reconstruction via tissue expander; of these, five (71%) completed permanent implant exchange prior to irradiation. Implant placement was pre-pectoral in twelve (75%). All patients received a dose of 50 Gy in 25 fractions; fifteen (94%) received a sequential boost to the mastectomy scar of a median 10 Gy. Fifteen (94%) used a near-surface contour (bound by the chest wall CTV, the skin surface, and the skin-3mm contour) for plan optimization to avoid dose to the near-surface region with a median value of the mean dose of 46.8 Gy. Acute grade > 2 radiation dermatitis was present in thirteen (81%) patients. Two (13%) experienced moist desquamation and ten (63%) experienced grade > 2 chest wall pain. Three (19%) underwent unplanned reconstructive surgery at a median time of 1.6 years post-treatment: all were capsulectomies due to capsular contracture. One (6%) patient experienced implant failure. A matched cohort of 59 patients who received photon irradiation was identified with a weighted median follow up of 2.5 years. The cohorts were similar with respect to rates of grade ≥2 radiation dermatitis, grade ≥2 chest wall pain, and unplanned reconstructive surgery. Proton irradiation resulted in statistically significant decreases in rates of moist desquamation (OR 0.01, 95% CI 0.0002-0.182) and implant failure (OR 0.01, 95% CI 0.0001-0.997). Post-mastectomy proton irradiation with prospective avoidance of the near-surface region in patients with implant-based reconstruction is feasible and well-tolerated; it results in low rates of unplanned reconstructive surgery and implant failure.

Surgical and patient-reported outcomes in an Asian female population with or without adjuvant radiotherapy after immediate free perforator flap breast reconstruction: A retrospective review

BackgroundThe majority of English literature has reported on the somewhat conflicted outcomes of the effect of radiotherapy on immediate breast reconstruction. However, data specifically related to patients of Asian descent has been scarce. This retrospective study aims to shed light on this topic to aid in the management of this group of patients. MethodsAll patients who received immediate free perforator flap-based breast reconstruction under a single surgeon over a 10-year period were included in the study. Patient characteristics, oncological and surgical data were collected. Patients were divided into post-mastectomy radiotherapy (PMRT) and non-PMRT groups. The final aesthetic outcome was assessed by a surgeon-reported outcome questionnaire. Patient satisfaction and psychological outcomes were assessed using validated patient-reported outcome (PRO) questionnaire (BREAST-Q), breast reconstruction, and postoperative module. ResultsA total of 101 women, with an average age of 44.7 ± 8.4 underwent perforator flap-based reconstruction. Fifteen patients received PMRT, with remaining 86 patients in the non-PMRT group. The mean duration of follow-up was over 5 years (p = 0.514). The recurrence rate was acceptable in the PMRT group (3/15, p = 0.129). There were no significant differences in complication rates between the two groups (p = 1.000). The aesthetic outcomes were comparable (p = 0.342). PRO appears to be lower in the PMRT group. ConclusionsImmediate breast reconstruction with PMRT in the local patient cohort is oncologically safe, acceptable complication profile, revision rate, and aesthetic outcome. PRO showed lower scores in several categories, which differ from normative data generated in the Western population. Further studies will need to examine the confounding effects of radiation in this specific population.

Conventional versus hypofractionated postmastectomy proton radiotherapy in the USA (MC1631): a randomised phase 2 trial

Proton therapy is under investigation in breast cancer as a strategy to reduce radiation exposure to the heart and lungs. So far, studies investigating proton postmastectomy radiotherapy (PMRT) have used conventional fractionation over 25-28 days, but whether hypofractionated proton PMRT is feasible is unclear. We aimed to compare conventional fractionation and hypofractionation in patients with indications for PMRT, including those with immediate breast reconstruction. We did a randomised phase 2 trial (MC1631) at Mayo Clinic in Rochester (MN, USA) and Mayo Clinic in Arizona (Phoenix, AZ, USA) comparing conventional fractionated (50 Gy in 25 fractions of 2 Gy [relative biological effectiveness of 1·1]) and hypofractionated (40·05 Gy in 15 fractions of 2·67 Gy [relative biological effectiveness of 1·1]) proton PMRT. All patients were treated with pencil-beam scanning. Eligibility criteria included age 18 years or older, an Eastern Cooperative Oncology Group performance status of 0-2, and breast cancer resected by mastectomy with or without immediate reconstruction with indications for PMRT. Patients were randomly assigned (1:1) to either conventional fractionation or hypofractionation, with presence of immediate reconstruction (yes vs no) as a stratification factor, using a biased-coin minimisation algorithm. Any patient who received at least one fraction of protocol treatment was evaluable for the primary endpoint and safety analyses. The primary endpoint was 24-month complication rate from the date of first radiotherapy, defined as grade 3 or worse adverse events occurring from 90 days after last radiotherapy or unplanned surgical interventions in patients with immediate reconstruction. The inferiority of hypofractionation would not be ruled out if the upper bound of the one-sided 95% CI for the difference in 24-month complication rate between the two groups was greater than 10%. This trial is registered with ClinicalTrials.gov, NCT02783690, and is closed to accrual. Between June 2, 2016, and Aug 23, 2018, 88 patients were randomly assigned (44 to each group), of whom 82 received protocol treatment (41 in the conventional fractionation group and 41 in the hypofractionation group; median age of 52 years [IQR 44-64], 79 [96%] patients were White, two [2%] were Black or African American, one [1%] was Asian, and 79 [96%] were not of Hispanic ethnicity). As of data cutoff (Jan 30, 2023), the median follow-up was 39·3 months (IQR 37·5-61·2). The median mean heart dose was 0·54 Gy (IQR 0·30-0·72) for the conventional fractionation group and 0·49 Gy (0·25-0·64) for the hypofractionation group. Within 24 months of first radiotherapy, 14 protocol-defined complications occurred in six (15%) patients in the conventional fractionation group and in eight (20%) patients in the hypofractionation group (absolute difference 4·9% [one-sided 95% CI 18·5], p=0·27). The complications in the conventionally fractionated group were contracture (five [12%] of 41 patients]) and fat necrosis (one [2%] patient) requiring surgical intervention. All eight protocol-defined complications in the hypofractionation group were due to infections, three of which were acute infections that required surgical intervention, and five were late infections, four of which required surgical intervention. All 14 complications were in patients with immediate expander or implant-based reconstruction. After a median follow-up of 39·3 months, non-inferiority of the hypofractionation group could not be established. However, given similar tolerability, hypofractionated proton PMRT appears to be worthy of further study in patients with and without immediate reconstruction. The Department of Radiation Oncology, Mayo Clinic, Rochester, MN, the Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA, and the US National Cancer Institute.

De-escalation of Post-mastectomy Irradiation in Hormone Receptor-Positive Breast Cancer with One to Three Positive Nodes.

The 21-gene recurrence score (RS) is used to predict benefit from chemotherapy in hormone receptor (HR)-positive breast cancer with one to three positive lymph nodes. Prospective-retrospective studies have shown that the RS is prognostic for both systemic and locoregional recurrence in tamoxifen-treated patients. We aimed to assess whether RS could be utilized to predict a survival benefit from postmastectomy radiation therapy (PMRT). The National Cancer Database (NCDB) was used to identify women ≤ 75 years of age with HR+, HER2-negative, T1-3, N1, M0 breast cancer who underwent mastectomy and axillary staging with available RS during the years 2010-2016. Kaplan-Meier and Cox proportional hazards models were used to identify association between treatment and overall survival (OS). Univariate and multivariate analyses were used to identify variables correlating with PMRT and OS. A total of 8907 patients were identified. Of the total, 3203 (36%) patients received adjuvant PMRT and 5704 (64%) did not. Across the entire cohort, 5-year OS was 97.5% for patients receiving PMRT and 96.8% for those who did not (P = 0.063). After adjusting for all covariates, in patients with RS ≤ 25, there was no statistically significant improvement in 5-year OS with the addition of adjuvant PMRT (97.5% versus 98.1% P = 0.093). Moreover, no survival benefit was seen with axillary node dissection (P = 0.58) or with the addition of chemotherapy (P = 0.312). In our cohort of patients with one to three positive nodes and a RS ≤ 25, omission of post-mastectomy radiation therapy had no impact on OS. Our results suggest that RS may be utilized in the individualized decision making on PMRT.

977 The Impact of Post-Mastectomy Radiotherapy on Immediate Free Flap Breast Reconstruction

Abstract Aim Radiotherapy following free flap breast reconstruction has historically been thought to increase complication rates, worsen patient reported outcomes (PROs) and lead to poorer cosmetic results. We aim to assess the impact post-mastectomy radiotherapy (PMRT) has on immediate free flap breast reconstruction using these variables, with patients acting as inherent controls. Method We conducted a retrospective cohort study on all patients receiving immediate bilateral free flap breast reconstruction followed by unilateral radiotherapy between 2008 and 2022. Complication rates were assessed by comparing prevalence of fat necrosis, volume depletion requiring lipofilling, and flap loss among irradiated vs non-irradiated breasts. PROs were assessed by comparing “Satisfaction with Breasts” and “Chest Physical Well-Being” (two sections of the Breast-Q survey) among irradiated vs non-irradiated breasts. Cosmetic outcomes were assessed by scoring postoperative pre-radiotherapy and postoperative post-radiotherapy patient images using “Objective Breast Cosmesis Scale” (OBCS) and “Harvard Breast Cosmesis Scale” (HBCS). Results 9 patients underwent immediate bilateral free flap breast reconstruction followed by unilateral radiotherapy. Median age was 40 years (IQR 32-44). Complication rates did not vary significantly between irradiated and non-radiated breasts. “Satisfaction with Breasts” did not vary significantly between irradiated and non-radiated breasts; however, “Chest Physical Well-Being” did vary significantly between both breasts. Cosmetic outcomes did not vary significantly between pre-radiotherapy and post-radiotherapy images. Conclusions PMRT following immediate free flap breast reconstruction does not have significant deleterious effects on complication rates, patient satisfaction with breasts or cosmetic outcomes. However, radiotherapy has a significant effect on patient’s chest physical well-being, hence we aim to study this further.

What are the effects of postmastectomy radiotherapy (PMRT) for women with early breast cancer and one to three positive lymph nodes?

What are the effects of postmastectomy radiotherapy (PMRT) for women with early breast cancer and one to three positive lymph nodes?